Prodrugs containing novel bio-cleavable linkers

ABSTRACT

The invention provides the compounds of formula (I) or pharmaceutically acceptable salts thereof. The invention also provides pharmaceutical compositions comprising one or more compounds of formula I or intermediates thereof and one more of pharmaceutically acceptable carriers, vehicles or diluents. The invention further provides methods of preparation and methods of use of prodrugs including NO-releasing prodrugs, double prodrugs and mutual prodrugs comprising the compounds of formula I.

This is a divisional of application Ser. No. 11/213,396 filed on Aug.26, 2005, now U.S. Pat. No. 7,932,294 claims the benefit thereof andincorporates the same by reference.

This application takes priority from US Provisional Application Ser. No.60/604,632 filed 26 Aug. 2004 and Indian Provisional Application779/MUM/2005 filed 1 Jul. 2005, which are herein incorporated in theirentirety.

FIELD OF THE INVENTION

The present invention relates to compositions of prodrugs, includingNO-releasing prodrugs, codrugs, double prodrugs and mutual prodrugs,containing bio-labile linkers and linkages, processes for theirpreparation and pharmaceutical compositions containing them and theiruse.

BACKGROUND OF THE INVENTION

A prodrug is an active drug chemically transformed into a per seinactive derivative which by virtue of chemical or enzymatic attack isconverted to the parent drug within the body before or after reachingthe site of action. The process of converting an active drug intoinactive form is called drug latentiation. Prodrugs can becarrier-linked-prodrugs and bioprecursors. The carrier-linked prodrugresults from a temporary linkage of the active molecule with a transportmoiety. Such prodrugs are less active or inactive compared to the parentactive drug. The transport moiety will be chosen for its non-toxicityand its ability to ensure the release of the active principle withefficient kinetics. Whereas the bioprecursors result from a molecularmodification of the active principle itself by generation of a newmolecule that is capable of being a substrate to the metabolizingenzymes releasing the active principle as a metabolite.

Prodrugs are prepared to alter the drug pharmacokinetics, improvestability and solubility, decrease toxicity, increase specificity, andincrease duration of the pharmacological effect of the drug. By alteringpharmacokinetics the drug bioavailability is increased by increasingabsorption, distribution, biotransformation, and excretion of the drug.Limited intestinal absorption, distribution, fast metabolism, andtoxicity are some of the causes of failure of drug candidates duringdevelopment. Avoidance of the foreseeable or proven pharmacokineticdefects thus assumes considerable significance in drug research.Accordingly, prodrugs play a significant role in drug research as well.

In designing the prodrugs, it is important to consider the followingfactors: a) the linkage between the carrier and the drug is usually acovalent bond, b) the prodrug is inactive or less active than the activeprinciple, c) the prodrug synthesis should not be expensive, d) theprodrug has to be reversible or bioreversible derivative of the drug,and e) the carrier moiety must be non-toxic and inactive when released.

Prodrugs are usually prepared by: a) formation of ester, hemiesters,carbonate esters, nitrate esters, amides, hydroxamic acids, carbamates,imines, mannich bases, and enamines of the active drug, b)functionalizing the drug with azo, glycoside, peptide, and etherfunctional groups, c) use of polymers, salts, complexes, phosphoramides,acetals, hemiacetals, and ketal forms of the drug. For example, seeAndrejus Korolkovas's, “Essentials of Medicinal Chemistry”, pp. 97-118.

The discovery and characterization of endothelium-derived nitric oxide(NO) was the subject of the 1998 Nobel Prize in Medicine and Physiology.NO is a major signaling molecule with important biological roles. See,for example, Kerwin, Jr., J. F. et al., J. Med. Chem. 1995, 38, 4343,and Williams. R. J. P., Chem. Soc. Rev., 1996, 77. The major biologicalfunctions of NO include controlling blood pressure, smoothing muscletone and inhibition of platelet adherence and aggregation, assisting theimmune system in destroying tumor cells and intracellular pathogens andparticipating in neuronal synaptic transmission. See, for example,Moncada, S. et al., Pharmacol. Rev. 1991, 43, 109; Bredt, D. S. et al.,Anuu. Rev. Biochem., 1994, 63, 175; Schmidt, H. H. W. et al., Cell 1994,78, 919; Feldman, P. L. et al., Chem. and Eng. News. 1993, 71 (20thDecember issue), 26; and Wilsonm E. K., Chem. and Eng. News. 2004(8^(th) March issue), 39. Endogenously, NO is produced from arginine bythe catalytic action of nitric oxide synthase. See, for example, Nathan,C. et al., Cell 1994, 78, 915, and Marietta, M. A., Cell 1994, 78, 927.

NO is a free radical as well as a scavenger of free radicals. NO reactsquickly with ubiquitously generated reactive oxygen species (ROS) suchas superoxide (O₂ ⁻) to generate a nefarious peroxynitrite (ONOO⁻)molecule, which is implicated in many human diseases such as diabetes,heart disease, Alzheimer's disease and multiple sclerosis. In thissetting, NO is often viewed as pathogenic. However, the chemistry of NOcan also be a significant factor in lessening the injury mediated byreactive oxygen species (ROS) and reactive nitrogen oxide species(RNOS). There is a relationship between NO and oxidation, nitrosationand nitration reactions. A number of factors determine whether NOpromotes, abates or interconnects these chemistries. See, for example,Espay, et al., A chemical perspective on the interplay between NO,reactive oxygen species, and reactive nitrogen oxide species, Ann N.Y.Acad. Sci. 2002, 962, 195.

Thus, by being a free radical, along with the ability to scavenge otherfree radicals, NO is placed in a pivotal regulatory position. Insightinto these pathophysiological processes and signaling are highlyrelevant to develop therapeutics.

NO deficiency has been implicated in the genesis and evolution ofseveral disease states. In patients with cardiovascular problems, theproduction of superoxide is increased and level or location of NOsynthesis is disrupted thereby causing cellular dysfunction as a resultof vasoconstriction of blood vessels, which can lead to, if prolonged,cell damage or death. Agents that act to maintain the normal balancebetween NO and superoxide in vascular endothelial cells may proveparticularly useful in this regard. See, for example, Stokes, K., etal., Free Radic. Bio. Med., 2002, 33, 1026-1036.

Nutritional and pharmacological therapies that enhance the bioactivityor production of NO have been shown to improve endothelium-dependentvasodilation, reduce symptoms, and slow the progression ofatherosclerosis. Some of the strategies for NO modulation encompassanti-inflammatory, sexual dysfunction, and cardiovascular indications.Apart from newly developed drugs, several commonly used cardiovasculardrugs exert their beneficial action, at least in part, by modulating theNO pathway. Pharmacological compounds that release NO have been usefultools for evaluating the pivotal role of NO in cardiovascular physiologyand therapeutics.

NO-Donors:

There are a wide variety of structurally dissimilar organic compoundsthat act as NO donors and release NO in solution. Some NO donors, suchas isoamyl nitrite, nitroglycerine (GTN) and sodium nitroprusside, havebeen used in cardiovascular medicine long before their biochemicalmechanism was understood. The common mode of action for these drugs isliberation of NO, which evokes relaxation of smooth muscle throughactivation of guanylate cyclase with subsequent formation of cGMP. Therelative importance of enzymatic versus non-enzymatic pathways for NOrelease, the identity of the actual NO-generating enzymes and theexistence of competing metabolic events are additional importantdeterminants of the different NO donor classes. Pharmacologicalcompounds that release NO constitute two broad classes of compounds:those that release NO or one of its redox congeners spontaneously andthose that require enzymatic metabolism to generate NO. See, forexample, Ignarro, L. J. et al., Nitric oxide donors and cardiovascularagents modulating the bioactivity of nitric oxide: an overview, Circ.Res. 2002, 90, 21-28.

Nitroglycerine/glycerine trinitrate (GTN) and compounds referred to asnitrovasodilators or NO donors are frequently used in the treatment ofischemic heart disease. The common mode of action for these drugs isliberation of NO, which evokes relaxation of smooth muscle throughactivation of guanylate cyclase with subsequent formation of cGMP.However, early development of tolerance to nitrate therapy, particularlyduring acute myocardial infarction, has been the clinically significantdrawback with GTN and some of the other available organic nitrates. Thisis a significant clinical problem and there exists a need for novelnitrate-based anti-anginal agents, which do not cause the problem ofnitrate tolerance.

There are a number of new examples of organic nitrates in which an alkylor aralkyl mononitrate is covalently linked to an existing drugmolecule. Existing drugs from a large number of therapeutic areas suchas anti-inflammatory, antiallergic, antibiotic, anticancer,antidiabetic, antiviral, antihypertensive, antianginal, anticonvulsant,analgesic, antiasthmatic, antidepressant, antidiarrheal, antiinfective,antimigraine, antipsychotic, antipyratic, antiulcerative,antithrombotic, etc., were made and evaluated. Some of Nicox's patentsinclude: Synthesis and evaluation of nitrooxy derivatives of NSAIDs (WO9412463, WO 0230867, WO 0292072, WO 0313499 and WO 0384550), aspirin (WO9716405, WO 0044705 and WO 0104082), paracetamol (WO 0112584 and WO0230866), antiepileptic agents (WO 0300642 and WO 0300643), COX-2inhibitors (WO 0400781 and WO 0400300), statins (WO 04105754), ACEinhibitors (WO 04110432 and WO 04106300), and of known drugs used forthe treatment of disease conditions resulting from oxidative stress andendothelial dysfunction (WO 0061537).

Most of these nitrate esters were shown to possess not only superior orequal efficacy when compared to the original drug but also exhibitmuch-reduced side effects. In fact, because of their superior efficacycombined with reduced toxicity, a few of such nitrate ester-containingdrug conjugates are successfully passing through various stages ofclinical trials. Some of Nicox's nitrooxy derivatives of drugs which arein clinical trials include: NCX 4016 (Phase II, peripheral vasculardiseases), NCX 701 (Phase II, Acute pain), HCT 1026 (Phase I,Alzheimer's disease), HCT 3012 (Phase II, Osteoarthritis), NCX 285 (IND,Osteoarthritis), NCX 1022 (Phase IIa completed, Dermatitis), NCX 1020(Phase I, Asthma/COPD), NCX 1000 (Phase I, Portal hypertension), and NCX1510 (Phase II, Allergic rhinitis).

U.S. Pat. No. 5,767,134 and US20050002942A1 disclosed a fewdisulfide-containing prodrugs/folate-drug conjugates. WO 9842661, U.S.Pat. No. 5,807,847, WO 0054756 and WO 0149275 reported a few nitrooxyderivatives of organic molecules containing sulfahydryl or disulfidegroup which are called “SS-nitrates”. These references are incorporatedherein by reference.

Representative examples from WO 9842661 have shown superior vasorelaxantactivity and no tolerance was observed to the cGMP-increasing effects ofthose compounds under the same experimental conditions used for theinduction of in vivo tolerance. WO 0149275 reports drug conjugates wherean anti-inflammatory drug is covalently linked to thebeta-mercapto-nitrate via thioester bond. Biotransformation pathwaysproposed for NO release from GTN have largely been heme-dependent orsulfahydryl-dependent. See, for examples, Thatcher, G. R. J. et al.,Chem. Soc. Rev. 1998, 27, 331 and reference cited therein, and Bennett,B M. et al., Trends Pharmacol, Sci. 1994, 15, 245. These references areincorporated herein by reference.

A mutual prodrug is the association in a unique molecule of two drugs,usually synergistic, attached to each other, one drug being the carrierfor the other and vice versa. The embodiments of the invention alsoprovide mutual prodrugs, which are prodrugs of two or three therapeuticagents currently used/potential for use in combination therapy utilizingnovel bio-cleavable linkers, water-soluble prodrugs ofinsoluble/sparingly-soluble therapeutic agents using the same linkertechnology and water-soluble double and triple prodrugs ofsparingly-soluble therapeutic agents or any of the prodrugs linked toNO-releasing agent using the same linker technology.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 shows plasma salicylate profile of aspirin and its NO-releasingprodrugs.

SUMMARY OF THE INVENTION

Present invention relates to the compounds of formula (I) orpharmaceutically acceptable salts thereof:

wherein,a is 0-2;B independently represents a bond, (CH₂)_(b), (CH₂CH₂O)_(c), S—S, S—S═O,S—SO₂ or S—S═NH;b is 1-6; c is 1-1000;A and A¹ independently represent a bond, (CH₂)_(d), 1,2-phenylene,1,3-phenylene or 1,4-phenylene;d is 1-8;D¹ represents a therapeutic agent comprising one or more of thefunctional groups selected from the group consisting of —OH, —SH, —NHR¹,—CO₂H, —CONHR¹, —OC(═O)NHR¹, —SO₂NHR¹, —OSO₂NHR¹, —N(R¹)C(═O)NHR¹ and—N(R¹)SO₂NHR¹;D² independently represents D¹, a peptide, protein, monoclonal antibody,vitamin, R², R³, R⁴, NO, NO₂, a linkable nitric oxide-releasing groupcomprising a NONOate, a group comprising one or more ofwater-solubilizing functional groups, or a polymer;E independently represents CH₂ or a bond;L¹ and L² independently represent a bond, O, S, NR¹, L, or a linkageselected from the group consisting of:

L is R¹² or a group with bonding in any direction, independentlyselected from the group consisting of:

X independently represents a bond, C, O, S, or NR¹;Y independently represents a bond, C═O, C═S, S═O, SO₂, P(═O)XR¹, or(CH₂)_(d);Z independently represents a bond, or (CH₂)₃; wherein, j is 1-4;R¹ independently represents a bond, H, (C₁-C₈)alkyl, (C₅-C₁₄)aryl,aralkyl or M^(e+);R² independently represents H, NH₂, or NHAc;R³ independently represents H, CO₂R⁵, CH₂CO₂R⁵,R⁴ independently represents H, OH, O—(C₁-C₈)alkyl, OM^(e+), or a groupselected from the group consisting of:

M independently represents Na, K or a pharmaceutically acceptable metalion,e=1-3,R⁵ independently represents at each occurrence H, M^(e+), (C₁-C₈)alkyl,(C₃-C₈)cycloalkyl, substituted (C₅-C₁₄)aryl, hetero(C₂-C₁₄)aryl,C(═O)(CH₂)_(f)CHR⁹CO₂R⁵, CH₂C(═O)OR⁵, P(═O)(OR⁵)₂,

X² independently represents O, S, SO, SO₂, or NR⁵;R⁶ independently represents H, Na⁺, K⁺, any other pharmaceuticallyacceptable metal ion, (C₁-C₈)alkyl, or (C₃-C₈)cycloalkyl,R⁷ independently represents at each occurrence same or different R⁵;R⁸ independently represents CH₂, O, NR⁴, S, S═O or O═S═O;R⁹ independently represents H, (C₁-C₈)alkyl or an amino acid;f is 0-6;g is 0-1;h is 1-2000;i is 1-4;R¹⁰ and R¹¹ independently represent H, (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl,or a group selected from the group consisting of:

with a proviso that when R¹⁰ is selected from the above group, R¹¹represents H or (C₁-C₈)alkyl, and when R¹¹ is selected from the abovegroup, R¹⁰ represents H or (C₁-C₈)alkyl;R¹² independently represents a group selected from the group consistingof:

and X³ is independently O or NR⁷.

Another embodiment of the invention is a pharmaceutical compositioncomprising one or more compounds of formula I or intermediates thereofand one or more of pharmaceutically acceptable carriers, vehicles ordiluents. Further embodiments include methods of preparation and methodsof use of prodrugs including NO-releasing prodrugs, double prodrugs andmutual prodrugs comprising the compounds of formula I.

DETAILED DESCRIPTION OF THE INVENTION

The present invention characterizes compositions, methods of preparationand methods of use of prodrugs, NO-releasing prodrugs, mutual prodrugs,double prodrugs, and codrugs.

The compounds of the present invention are prodrugs or mutual prodrugsin which known therapeutic agents or potential therapeutic agents arelinked covalently to novel biocleavable linkers.

The compounds of the present invention also include NO-releasingprodrugs in which a therapeutic agent is linked covalently to nitrooxy(nitrate ester) group via a novel bio-cleavable linker containing astrategically placed disulfide group at β-position to the nitrate ester.The present invention also characterizes composition of NO-releasingprodrugs (i.e., nitrooxy ester or nitrate ester prodrugs), processes fortheir preparation, pharmaceutical composition containing them and theiruse.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Listed below are definitions ofvarious terms used to describe the compounds of the present invention.These definitions apply to the term as they are used throughout thespecification (unless they are otherwise limited in specific instances)either individually or part of a larger group.

The term “amino-containing” refers to drug/carrier molecule with NHfunctional groups such as amino (both primary and secondary), amide,urea, sulfonamide, carbamate, phosphoramadite, sulfamate, hydrazone,semicarbazone, thiosemicarbazone, hydrazide, carbazate and the like.This also includes NH-containing heterocylic compounds such asimidazoles, benzimidazoles, pyrazoles, benzpyrazols, pyrrols, indoles,triazoles, tetrazoles, benzotriazoles, benzotetrazoles and theirderivatives. These NH-containing heterocyclic compounds can besub-structures of more complex drug/carrier molecules. Amino group ofthe candidate drug can be primary or secondary (both acyclic and cyclic)which include amide-NH, sulfonamide-NH, carbamate-NH, sulfamate-NH,hydrazide-NH, hydrazone-NH, semicarbazone-NH, thiosemicarbazone-NH,urea-NH and also drugs containing indole, imidazole, benzimidazole,thiazole, oxazole, pyrrole, pyrazole, triazole, tetrazole, or similarNH-containing heterocylic sub-structures of a more complex drugmolecule.

The term “hydroxyl-containing” refers to drug/carrier molecules withhydroxyl groups (primary, secondary, tertiary and phenolic) includinghydroxyl groups of hydroxamic acids and ketoximes derived fromketo-containing molecules. Hydroxyl group of drugs can be of primary,secondary, tertiary or phenolic in nature.

The term “sulfahydryl-containing” refers to drug/carrier with freesulfahydryl (SH) group.

The term “halo” refers to fluoro, chloro, bromo, and dodo.

The term “halide” refers to fluoride, chloride, bromide, and iodide.

The term “alkyl” refers to acyclic alkyl chains. For example, the term“C₁-C₈ alkyl” refers to methyl, ethyl, propyl, isopropyl, butyl,cyclobutyl, s-butyl, and t-butyl, pentyl, hexyl, heptyl, octyl, and thelike.

The term “cycloalkyl” refers to cyclic alkyl chains, e.g., the term“C₃-C₈ cycloalkyl” refers to cyclopropyl, cyclooctyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl and the like.

The term “aryl” refers to phenyl, naphthyl and the like.

The term “aralkyl” refers to benzyl, phenethyl and the like.

The term “alkoxy” refers to both acyclic and cyclic C₁-C₈ alkyloxy. Forexample, the term “C₁-C₈ alkyloxy” refers to methoxy, ethoxy, propoxy,isopropoxy, cyclopropoxy, butoxy, cyclobutoxy, s-butoxy, and t-butoxy,cyclopentyloxy, pentyloxy, hexyloxy, cyclohexyloxy, heptyloxy,cycloheptyloxy, octyloxy, cyclooctyloxy and the like.

The term “heterocyclic” and “heteroaryl” refers to both saturated andunsaturated 5- and 6-membered rings (including benzo-fused) containingfrom 1 to 4 heteroatoms selected from the group consisting of nitrogen,oxygen and sulfur. All of these rings may be substituted with up tothree substituents independently selected from the group consisting ofamino, halo, alkoxy, alkyl, cyano, nitro, hydroxyl, sulfahydryl,carboxyl and the like. Saturated rings include, for example,pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuryl, oxazolidinyl,dioxanyl, pyranyl, and the like. Benzofused saturated rings includeindolinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyland the like. Unsaturated rings include furyl, thienyl, pyridinyl,pyrrolyl, N-methylpyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl,tetrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl,pyrimidinyl, pyrazinyl, pyridazinyl, and the like. Benzofusedunsaturated rings include isoquinolinyl, benzoxazolyl, benzthiazolyl,quinolinyl, benzofuranyl, thionaphthyl, indolyl and the like.

The term “substituted alkyl” refers to acylic and cyclic alkyl groupssubstituted with one or more of groups such as alkyl, aryl, hydroxy,alkoxy, cyano, carboxyl, sulfahydryl, alkylthio, amino, nitro, halo,carbonyl, carbamato, sulfamato, sulfonato, sulfato, and the like.

The term “substituted aryl” refers to aryl groups substituted (includingfused) with one or more of groups such as alkyl, aryl, hydroxy, alkoxy,cyano, carboxyl, sulfahydryl, alkylthio, amino, nitro, halo, carbonyl,carbamato, sulfamato, sulfonato, sulfato, and the like.

The term “amino acid” refers to molecules containing one or more aminoand carboxyl groups. Examples of alfa-amino acids (D-, L- and DL-aminoacids)-include natural alanine, arginine, asparagine, aspartic acid,cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine,leucine, lysine, methionine, phenylalanine, proline, serine, threonine,tryptophan, tyrosine, and valine. Other examples include beta-aminoacids and known unnatural amino acids.

The term “amino acid ester” as used in this specification refers to anamino acid where the carboxyl group is substituted with a C₁-C₈ alkylgroup. That is, the alkyl group when taken together with the carboxylgroup forms a C₁-C₆ alkyl ester. It is appreciated that some amino acids(e.g., aspartic acid and glutamic acid) have two carboxyl groups thesemay form mono- and di-esters.

The term “protecting group” (PG) refers to an ‘amino protecting group’or a ‘hydroxyl protecting group’ or a ‘carboxyl protecting group’ andthe like.

The term “amino protecting group” refers to a group that selectivelyblocks or protects the amino functionality in presence of otherfunctional groups on the molecule. Examples of such amino-protectinggroups include the formyl group, the trityl group, the phthalimidogroup, the acetyl group, the trifluoroacetyl group, the chloroacetyl,bromoacetyl, and iodoacetyl groups, urethane-type blocking groups suchas benzyloxycarbonyl (“CBZ”), 9-fluorenylmethoxycarbonyl (“FMOC”),tert-butoxycarbonyl (“BOC”), trichloroethylcarbonyl and the like.Additional examples of amino protecting groups are described by T. W.Greene, “Protective Groups in Organic Synthesis”, John Wiley and Sons,New York, N.Y., 1991. Molecules with two or more amino groups may formmono-, di-, tri-, poly-, protected derivatives depending on the reactionconditions used.

The term “hydroxyl protecting group” refers to a group that selectivelyblocks or protects hydroxyl functionality in presence of other reactivefunctional groups on the molecule. Examples of such hydroxyl-protectinggroups include, for example, ether groups including methyl andsubstituted methyl ether groups such as methyl ether, methoxymethylether, methylthiomethyl ether, tert-buylthiomethyl ether,triphenylmethyl, tetrahydropuranyl (THP),(phenyldimethylsilyl)methoxy-methyl ether, benzyloxymethyl ether,p-methoxybenzyloxy-methyl ether, and tert-butoxymethyl ether;substituted ethyl ether groups such as ethoxyethyl ether,1-(2-chloroethoxy)-ethyl ether, 2,2,2-trichloroethoxymethyl ether, and2-(trimethylsilyl)ethyl ether; isopropyl ether groups; phenyl andsubstituted phenyl ether groups such as phenyl ether, p-chlorophenylether, p-methoxyphenyl ether, and 2,4-dinitrophenyl ether; benzyl andsubstituted benzyl ether groups such as benzyl ether, p-methoxybenzylether, o-nitrobenzyl ether, and 2,6-dichlorobenzyl ether; and alkylsilylether groups such as trimethyl-, triethyl- and triisopropylsilyl ethers,mixed alkylsilyl ether groups such as dimethylisopropylsilyl ether,tert-butyldimethylsilyl ether and diethylisopropylsilyl ether; and esterprotecting groups such as acetate ester, formate ester, benzylformateester, mono-, di-, and trichloroacetate esters, pivalate ester,phenoxyacetate ester, and p-chlorophenoxyacetate, benzyloxycarbonate,9-fluorenylmethoxycarbonate, tert-butoxycarbonate,trichloroethylcarbonate, carbamate, sulfamate and the like. Additionalexamples of hydroxyl protecting groups are described by T. W. Greene,“Protective Groups in Organic Synthesis”, John Wiley and Sons, New York,N.Y., 1991. Molecules with two or more hydroxyl groups may form mono-and di-esters/ethers depending on the reaction condition.

The term “carboxyl protecting group” refers to a group that selectivelyblocks or protects carboxyl functionality in presence of other reactivefunctional groups on the molecule. Examples of such carboxyl-protectinggroups include, for example (substituted) alkyl esters such methylester, ethyl ester, t-butyl ester, (substituted) benzyl ester,trichloroethyl ester, and the like. Additional examples of carboxylicacid protecting groups are described by T. W. Greene, “Protective Groupsin Organic Synthesis”, John Wiley and Sons, New York, N.Y., 1991.Molecules with two or more carboxylic acid groups may form mono-, di-,tri-, tetra-, poly-protected derivatives depending upon the reactionconditions used.

The term “carbonyl activating group” refers to leaving group (“LG”) of acarboxyl derivative that is easily replaced by an incoming nucleophile.Such “LG” groups include, but are not limited to, (substituted) alkoxy,aryloxy, nitrogen containing unsaturated heterocycles such asN-oxybenzotriazole, imidazolyl, o/p-nitrophenoxy, pentachloro-phenoxy,N-oxysuccinimide, N,N′-dicyclohexylisoure-O-yl,N-hydroxy-N-methoxyamino, and the like; acetates, formates, sulfonatessuch as methanesulfonate, ethanesulfonate, benzenesulfonate, orp-toluenesulfonate, and the like; and halides especially fluoride,chloride, bromide, or iodide.

The term “carbonyl activating reagent” refers to a reagent that convertsthe carbonyl of a carboxylic acid group into one that is moresusceptible to nucleophilic attack and includes, but is not limited to,such reagents as those found in “The Peptides”, Gross and Meienhofer,Eds., Academic Press (1979), Ch. 2, and M. Bodanszky, “Principles ofPeptide Synthesis”, 2.sup.nd Ed., Springer-Verlag Berlin Heidelberg,1993, hereafter referred to as “The Peptides” and “Peptide Synthesis”respectively. Carbonyl group (i.e., aldehyde or keto group) of candidatedrugs may be converted first to aldoxime, ketoxime, hydrazone,semicarbazone and the like, before coupling to the linker. Specifically,carbonyl activating reagents include thionyl bromide, thionyl chloride,oxalyl chloride, and the like; esters of alcohols such as nitrophenol,pentachlorophenol, and the like; and compounds such as1,1′-carbonyldiimidazole (CDI), benzotriazole, imidazole,N-hydroxysuccinimide, dicyclohexylcarbodiimide (DCC), EDC, phosgene orits equivalents, N,N-dimethylaminopyridine (DMAP) and the like.

The terms “phosgene or its equivalents” refer to phosgene or itequivalents such as diphosgene, triphosgene, CDI, DSC, BTBC,alkoxycarbonyl chlorides, o/p-nitrosubstituted phenoxycarbonylchlorides, and the like.

In general, the term “pharmaceutical” when used as an adjective meanssubstantially non-toxic to living organisms.

The terms “pharmaceutically acceptable metal ions or salts” refer tosalts of the compounds of this invention, which are substantiallynon-toxic to living organisms. See, e.g., Berge, S. M. et al.,“Pharmaceutical Salts”, J. Pharm. Sci., 66:1, 1977. Typicalpharmaceutical salts include those salts prepared by reaction of thecompounds of this invention with an inorganic or organic acid or base.Such salts are known as acid addition or base addition saltsrespectively. These pharmaceutical salts frequently have enhancedsolubility characteristics compared to the compound from which they arederived, and thus are often more amenable to formulation as liquids oremulsions. Examples of pharmaceutically acceptable salts are those withinorganic bases such as sodium, potassium, calcium, magnesium, andhydroxides, and the like, or with organic bases such as lysine,arginine, triethylamine, dibenzylamine, piperidine, and the like.

The term “suitable solvent” refers to a solvent that is inert to theongoing reaction and sufficiently solubilizes the reactants to effectthe desired reaction. Examples of suitable solvents include but are notlimited to, dichloromethane, chloroform, 1,2-dichloroethane, diethylether, tert-butylmethyl ether, acetonitrile, ethyl acetate,1,3-dimethyl-2-imidazolidindne, tetrahydrofuran, dimethylformamide,benzene, toluene, xylene, N-dimethylacetamide, N-methylpyrrolidine,chlorobenzene, dimethylsulfoxide, dimethoxyethane, water, methanol,ethanol, isopropanol, pyridine, nitromethane, mixtures thereof, and thelike.

The term “suitable base” refers to a base, which acts as a proton trapfor any protons, which may be produced as a byproduct of the desiredreaction, or to a base, which provides a reversible deprotonation of anacidic proton from the substrate and is reactive enough to effect thedesired reaction without significantly effecting any undesiredreactions. Examples of such bases include, but are not limited to,carbonates, bicarbonates, and hydroxides (e.g., lithium, sodium,potassium, magnesium, calcium and the like), sodium/potassium/calciumhydride, sodium/potassium alkoxide (i.e., methoxide, ethoxide,tert-butoxide and the like), triethylamine, diisopropylethylamine,N-methylpyrrolidine, N-methylmorpholine, tetramethylguinidine, oraromatic nitrogen containing heterocycles such pyridine,4-(dimethylamino)pyridine (DMAP), and the like.

The term “NONOate” refers to a linkable nitric oxide-releasing groupsuch as AcOCH₂—O—N₂—N(O⁻)R⁷, OCHOCH₂—O—N₂—N(O⁻)R⁷R⁷, CH₂—O—N₂—N(O⁻)R⁷R⁷and the like.

The term “therapeutic agent” refers to biologically active moleculessuch as drugs, vitamins, and other molecules, agents or substancesconcerned with or contributing to the treatment and cure of illness orcontributing to the general well being of a mammal or human. Thetherapeutic agents can be both known and investigational drugs compiledin drug databases such as the Merck Index, IDdb, Prous Science'sIntegrity®, Prous Science Drugs of the Future™, The Ensemble® and thelike. The Merck Index is a one-volume encyclopedia of chemicals, drugsand biologicals that contains more than 10,000 monographs. Eachmonograph in this authoritative reference source is a concisedescription of a single substance or a small group of closely relatedcompounds. Prous Science is an international health science publishingcompany, established in 1958 and headquartered in Barcelona, Spain.Prous Science Drugs of the Future™, produced by Prous SciencePublishers, contains comprehensive drug monographs providing productinformation on new compounds, including the synthesis and correspondingschemes, pharmacological action, pharmacokinetics and metabolism,toxicity, clinical studies, manufacturer, and references. Information oncompounds is continuously updated as advances in development status aredisclosed worldwide. The Prous Science Integrity™ is a drug R&D portalwhere knowledge areas are coordinated to provide a harmonious andinterrelated whole, which includes Drugs & Biologics, Targets, OrganicSynthesis, Experimental Pharmacology, Pharmacokinetics and Metabolism,Clinical Studies, Disease Briefings, Companies & Markets, Literature andPatents. The Investigational Drugs database (IDdb), developed by ThomsonCurrent Drugs, is a pharmaceutical competitor intelligence service. Itcovers all aspects of investigational drug development, from firstpatent to eventual launch or discontinuation. The Ensemble® on the Webprovides essential information, including chemical structures, on morethan 140,000 compounds with demonstrated biological activity in the drugresearch and development pipeline.

The term “vitamin” includes vitamin A, vitamin C, thiamine, folic acid,biotin, inositol, nicotinic acid, nicotinamide, riboflavin, pyridoxine,pyridoxal 5-phosphate, ergosterol, vitamin D2, vitamin D3, vitamin D4,vitamin E, menadoxime, menadiol, and vitamin K5.

The term “peptide” includes large and small peptides, including, but notlimited to, targetable small peptides such as a dipeptide, tripeptide,tetrapeptide, etc.

The term “ligand” means a small molecule that binds to a largermacromolecule, whether or not the ligand actually binds at a metal site.Such ligands can be small peptides.

One aspect of the invention is to provide mutual prodrugs of two orthree therapeutic agents currently used for use in combination therapyutilizing novel bio-cleavable linkers, water-soluble prodrugs ofinsoluble and sparingly-soluble therapeutic agents using the same linkertechnology, and water-soluble double and triple prodrugs ofsparingly-soluble therapeutic agents using the same linker technology.The embodiments of the invention may also comprise vitamins andtargetable small peptides in addition to or in place of a promoeity toyield targetable prodrugs.

The candidate drugs selected for mutual prodrug synthesis can be fromone therapeutic category or from different therapeutic categories.Similarly, the constituent drugs of a mutual prodrug can act on the samebiological target with similar mechanism of action or act on differentbiological targets with different mechanisms of action.

To be considered for prodrug synthesis, the candidate drugs shouldcontain one or more of the essential functional groups such as amino,hydroxyl, keto, or carboxyl groups in their structure.

Amino group of the candidate drug can be primary or secondary (bothacyclic and cyclic) which include amide-NH, sulfonamide-NH,carbamate-NH, sulfamate-NH, hydrazone-NH, semicarbazone-NH,thiosemicarbazone-NH and also drugs containing indole, imidazole,benzimidazole, thiazole, oxozole, pyrrole, pyrazole, triazole,tetrazole, or similar NH-containing heterocylic sub-structures of a morecomplex drug molecule. Similarly, hydroxyl group of drugs can be ofprimary, secondary, tertiary or phenolic in nature. Keto group ofcandidate drugs may be converted first to ketoxime, hydrazone,semicarbazone and the like, before coupling to the linker. Obviously,hydroxyl or amino functions thus generated will be used to form covalentbond between the drug and the linker.

The candidates for making mutual prodrugs can be the pairs of drugs thatare currently used in combination therapy (including those combinationstudies at investigational stage) in various therapeutic areas providedeach of those drugs possesses the requisite functional group(s). Thereare a number of therapeutic areas where such combination therapy isapplied routinely and successfully.

On the basis of the proposed sulfahydryl-dependent mechanism ofNO-release from GTN, we have designed the compounds and prodrugs of thepresent invention where a suitable drug molecule is linked covalently toa nitrooxy (nitrate ester) group via a bio-labile linker containingstrategically located disulfide bond at beta-position to nitrate ester.In vivo, the disulfide bond in the prodrug is expected to be reduced byendogenous sulfahydryl-containing species such as glutathione (GSH) togenerate a reactive thiolate anion (i.e., beta-mercapto-nitrate), whichcan trigger further break-down of the linker moiety to release the freedrug (via a mechanism as shown Scheme M1) and NO simultaneously at thesame location. It is possible, as depicted in the mechanism Scheme M1,the release of NO can go via a hypothetical cyclic transientintermediate ‘b’. Similar hypothetical mechanism was proposed for NOrelease from SS-nitrates, which were also designed on the basis of asulfahydryl-dependent NO release from GTN. See, for example, Zavorin, S.I. et al., Organic Letters, 2001, 3, 1113, incorporated herein in itsentirety. Mutual prodrugs can be made by linking covalently any two ofthe following: an amino-containing therapeutic agent to anotheramino-containing therapeutic agent; an amino-containing therapeuticagent to a hydroxyl-containing therapeutic agent; an amino-containingtherapeutic agent to a carboxyl-containing therapeutic agent and itsderivative; a hydroxyl-containing therapeutic agent to acarboxyl-containing therapeutic agent and its derivative; anamino-containing therapeutic agent to a carboxyl-containing therapeuticagent and its derivative; an amino-containing therapeutic agent to aketo-containing therapeutic agent or its hydrazone, semicarbazone oroxime derivative and the like; a hydroxyl-containing therapeutic agentto a keto-containing therapeutic agent via its hydrazone, semicarbazone,or oxime derivative and the like.

Another aspect of the present invention is to provide new nitrate ester(NO-releasing) prodrugs of many types of existing drugs using novelbiocleavable linkers. Such prodrugs are expected to exhibit betterefficacy and tolerability with reduced side effects compared to thecorresponding original drugs.

An embodiment of present invention relates to the compounds of formula(I) or pharmaceutically acceptable salts thereof:

wherein,a is 0-2;B independently represents a bond, (CH₂)_(b), (CH₂CH₂O)_(c), S—S, S—S═O,S—SO₂ or S—S═NH;b is 1-6; c is 1-1000;A and A¹ independently represent a bond, (CH₂)_(d), 1,2-phenylene,1,3-phenylene or 1,4-phenylene;d is 1-8;D¹ represents a therapeutic agent comprising one or more of thefunctional groups selected from the group consisting of —OH, —SH, —NHR¹,—CO₂H, —CONHR¹, —OC(═O)NHR¹, —SO₂NHR¹, —OSO₂NHR¹, —N(R¹)C(═O)NHR¹ and—N(R¹)SO₂NHR¹;D² independently represents D¹, a peptide, protein, monoclonal antibody,vitamin, R², R³, R⁴, NO, NO₂, a linkable nitric oxide-releasing groupcomprising a NONOate, a group comprising one or more ofwater-solubilizing functional groups, or a polymer;E independently represents CH₂ or a bond;L¹ and L² independently represent a bond, O, S, NR¹, L, or a linkageselected from the group consisting of:

L is R¹² or a group with bonding in any direction, independentlyselected from the group consisting of:

X independently represents a bond, C, O, S, or NR¹;Y independently represents a bond, C═O, C═S, S═O, SO₂, P(═O)XR¹ or(CH₂)_(d);Z independently represents a bond, or (CH₂)_(j); wherein, j is 1-4;R¹ independently represents a bond, H, (C₁-C₈)alkyl, (C₅-C₁₄)aryl,aralkyl or M^(e+);R² independently represents H, NH₂, or NHAc;R³ independently represents H, CO₂R⁵, CH₂CO₂R⁵,R⁴ independently represents H, OH, O—(C₁-C₈)alkyl, OM^(e+), or a groupselected from the group consisting of:

M independently represents Na, K or a pharmaceutically acceptable metalion,e=1-3,R⁵ independently represents at each occurrence H, (C₁-C₈)alkyl,(C₃-C₈)cycloalkyl, substituted (C₅-C₁₄)aryl, hetero(C₂-C₁₄)aryl,C(═O)(CH₂)_(f)CHR⁹CO₂R⁵, CH₂C(═O)OR⁵, P(═O)(OR⁵)₂,

X² independently represents O, S, SO, SO₂, or NR⁵;R⁶ independently represents H, Na⁺, K⁺, any other pharmaceuticallyacceptable metal ion, (C₁-C₈)alkyl, or (C₃-C₈)cycloalkyl,R⁷ independently represents at each occurrence same or different R⁵;R⁸ independently represents CH₂, O, NR⁴, S, S═O or O═S═O;R⁹ independently represents H, (C₁-C₈)alkyl or an amino acid;f is 0-6;g is 0-1;h is 1-2000;i is 1-4;R¹⁰ and R¹¹ independently represent H, (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl,or a group selected from the group consisting of:

with a proviso that when R¹⁰ is selected from the above group, R¹¹represents H or (C₁-C₈)alkyl, and when R¹¹ is selected from the abovegroup, R¹⁰ represents H or (C₁-C₈)alkyl;R¹² independently represents a group selected from the group consistingof:

X³ is independently O or NR⁷.

D¹ and D² of the present invention can be both known and investigationaldrugs compiled in drug databases such as the Merck Index, IDdb, ProusScience's Integrity®, Prous Science Drugs of the Future™, The Ensemble®and the like. In a double prodrug, D¹ and D² are the same drugs. In amutual prodrug, D¹ and D² are different drugs. In some prodrugs, only D1is a drug and D² may not be a drug at all. The —OH, —SH, —NH₂, —NHR¹,—CO₂H, —CONHR¹, —OC(═O)NHR¹, —SO₂NHR¹, —OSO₂NHR¹, —N(R¹)C(═O)NHR¹ and—N(R¹)SO₂NHR¹ functional groups in D¹ and D² of formula I participate inthe formation of linkages between the drug and the linker. Accordingly,some of the atoms or groups in L¹ and L² may come from the correspondingD¹, D² or linker.

Another embodiment of the invention is the compound of formula I,wherein D² is an amino-, carboxyl- or hydroxyl-containing group ormolecule comprising one or more water solubilizing functional groupsselected from the group consisting of hydroxyl, amino, acylamino,carboxyl, sulphate, sulfonate, phosphate, phosphonate,N-acylsulfonamide, N-acylsulfamate, N-acylcarbamate, N-acylcarbamatemetallic salts, and amino acids to give water-soluble prodrug.

Another embodiment of the invention is the compound of formula I,wherein D² is selected from the group of D, L and DL amino acidsconsisting of Alanine, Arginine, Asparagine, Aspartic acid, Cysteine,Glutamine, Glutamic acid, Glycine, Histidine, Isoleucine, Leucine,Lysine, Methionine, Phenylalanine, Proline, Serine, Threonine,Tryptophan, Tyrosine, and Valine.

Another embodiment of the invention is the compound of formula I,wherein D² represents a polymer selected from the group consisting ofarabinogalactan, polyamino acids, polyethylene glycol, polycaprolactone,polyglycolic acid, polylactic acid, polyacrylic acid,poly(2-hydroxyethyl 1-glutamine), dextran and modified dextrans such asdextran aldehyde, carboxymethyl dextran, arabinogalactane aldehyde,carboxymethyl arabinogalactane, and hyaluronic acid.

Yet another embodiment of the invention is the compound of formula I,wherein D² is a polyaminoacid selected from group consisting ofpoly(l-glutamic acid), poly(d-glutamic acid), poly(dl-glutamic acid),poly(l-aspartic acid), poly(d-aspartic acid), poly(dl-aspartic acid),copolymers of the polyaminoacids and polyethylene glycol.

Another embodiment of the invention is the compound of formula I,wherein the polymer has a molecular weight of about 5000 to about100,000 Daltons. Yet another embodiment of the invention is the compoundof formula I, wherein the polymer has a molecular weight of about 10,000to about 50,000 Daltons.

In a further embodiment D² is a peptide, protein or monoclonal antibodyfor achieving targeted delivery of prodrugs and drugs. Anotherembodiment of the invention is the compound of formula I, wherein D² isa ligand or dipeptide or a dipeptide ligand. In a further embodiment D²is a dipeptide ligand that is a substrate for intestinal transportersfor selective intestinal absorption of the corresponding prodrugsthereby increasing the bioavailability of the prodrugs. In a furtherembodiment D² is a targetable small peptide, i.e., dipeptide,tripeptide, tetrapeptide, etc.

Another embodiment of the invention is the compound of formula I,wherein D² is a vitamin. Such vitamin-conjugated prodrugs are expectedto be taken up by the diseased cells via receptor-mediated endocytosis.In a further embodiment of the invention is a compound of formula I,wherein D² is selected from the group of vitamins consisting of vitaminA, vitamin C, thiamine, folic acid, biotin, inositol, nicotinic acid,nicotinamide, riboflavin, pyridoxine, pyridoxal 5-phosphate, ergosterol,vitamin D2, vitamin D3, vitamin D4, vitamin E, menadoxime, menadiol, andvitamin K5.

Another embodiment of the invention is the compound of formula I,wherein D¹ and D² represent the same therapeutic agent to give asymmetrical double prodrug. Another embodiment of the invention is thecompound of formula I, wherein D¹ and D² represent different therapeuticagents to give a mutual prodrug. Another embodiment of the invention isthe compound of formula (I), wherein D¹ and D² can be either from sameor different therapeutic class. Another embodiment of the invention isthe compound of formula (I), wherein D¹ and D² can be same or differenttherapeutic agents. Such therapeutic agents may have same or differentmechanisms of action or they may work on different biological targets orwork on different disease conditions.

Another embodiment of the invention is the compound of formula I,wherein D² is R², R³ or R⁴. Another embodiment of the invention is thecompound of formula I, wherein a is 0, B is S—S, S—S═O, S—SO₂ or S—S═NH.Yet another embodiment of the invention is the compound of formula I,wherein a is 0, B is S—S or S—S═O, S—SO₂ and D² is R² or R³ or R⁴. Afurther embodiment of the invention is the compound of formula I,wherein B is S—S, A and A¹ are CH₂—CH₂, E is a bond and D² is R², R³ orR⁴.

Another embodiment of the invention is the compound of formula I,wherein a is 0; B is S—S or S—S═O, S—SO₂; A and A¹ are CH₂—CH, E is abond and D² is R⁴. Another embodiment of the invention is the compoundof formula I, wherein a is 0; B is S—S; A and A¹ are CH₂—CH₂, E is abond and D² is R⁴.

Another embodiment of the invention is the compound of formula I,wherein a is 0, B is a bond, (CH₂)_(b), or (CH₂CH₂O)_(c); wherein b andc are as defined above. Another embodiment of the invention is thecompound of formula I, wherein a is 0, B is a bond, (CH₂)_(b) or(CH₂CH₂O)_(c) and D² is R² or R³ or R⁴; wherein b and c are as definedabove.

Yet another embodiment of the invention is the compound of formula I,wherein a is 0; B is S—S or S—S═O, S—SO₂; D¹ and D² are drug molecule orR² or R⁴ containing carboxyl group; L¹ and L² are independently selectedfrom the following linkages:

wherein, X, R¹, Z are as defined above; and Y is C═O. In anotherembodiment, A and A¹ are CH₂—CH₂ and E is a bond. In a furtherembodiment, A and A¹ are 1,2-phenylene, 1,3-phenylene or 1,4-phenyleneand E is CH₂.

Yet another embodiment of the invention is the compound of formula I,wherein a is 0; B is S—S or S—S═O, S—SO₂; D¹ and D² are drug molecule orR² or R⁴ containing amino- or hydroxyl group; L¹ and L² areindependently selected from the following linkages:

wherein, X, R¹, Z are as defined; and Y is C═O. In another embodiment, Aand A¹ are CH₂—CH₂, and E is a bond. In a further embodiment, A and A¹are 1,2-phenylene, 1,3-phenylene or 1,4-phenylene, and E is CH₂.

Yet another embodiment of the invention is the compound of formula I,wherein a is 0, B is S—S or S—S═O, S—SO₂ and D² is D¹. Anotherembodiment of the invention is the compound of formula I, wherein a is0; B is S—S or S—S═O, S—SO₂; A and A¹ are CH₂—CH₂, E is a bond and D² isD¹. Another embodiment of the invention is the compound of formula I,wherein a is 0; B is S—S or S—S═O, S—SO₂; A and A¹ are 1,2-phenylene,1,3-phenylene or 1,4-phenylene; E is CH₂ and D² is D¹ or R² or R³ or R⁴.Another embodiment of the invention is the compound of formula I,wherein a is 0; B is S—S; A and A¹ are 1,2-phenylene, 1,3-phenylene or1,4-phenylene; E is CH₂ and D² is D¹ or R² or R³ or R⁴. A furtherembodiment of the invention is the compound of formula I, wherein B isS—S, A and A¹ are CH₂—CH₂, E is a bond and D² is D¹.

Yet another embodiment of the invention is the compound of formula I,wherein a is 0; B is S—S or S—S═O, S—SO₂; A and A¹ are CH₂—CH₂, E is abond and D² is a dipeptide ligand. Yet another embodiment of theinvention is the compound of formula I, wherein a is 0; B is S—S; A andA¹ are CH₂—CH₂, E is a bond and D² is a dipeptide ligand. The peptideligands used in the invention can be substrates for intestinaltransporters for selective intestinal absorption of the correspondingprodrugs thereby increasing the bioavailability of the prodrugs. Anembodiment of the present invention is the compounds of formula (I),wherein D¹, L¹ and L² are as defined above; A and A¹ are CH₂; E is CH₂;B is a bond or (CH₂)_(b); b is 1-6; a is 0; and D² is D¹ or R² or R⁴.

Another embodiment of the present invention is the compound of formula(I), wherein E, D¹ and L¹ are as defined; L² is O; A and A¹ areindependently (CH₂)_(d), 1,2-phenylene, 1,3-phenylene, or 1,4-phenylene;d is 1-4; B is S—S, S—S═O, S—SO₂ or S—S═NH; a is 0; D² is NO, NO₂ or anitric oxide releasing molecule such as NONOate. In a furtherembodiment, D² is a NONOate selected from the group consisting of:

In yet another embodiment, when D² is one of the above NONOates, B isS—S.

Another embodiment of the present invention is the compound of formula(I), L² is O; A and A¹ are independently (CH₂)_(d), 1,2-phenylene,1,3-phenylene, or 1,4-phenylene; d is 1-4; B is S—S; a is 0; D² is NO₂.In a further embodiment, when A and A¹ CH₂—CH₂, E is a bond. In yetanother embodiment, when E is CH₂, A and A¹ are independently1,2-phenylene, 1,3-phenylene, or 1,4-phenylene.

Yet another embodiment of the present invention is the compound offormula (I), wherein D¹ is an amino containing drug molecule having thefollowing reactive functional groups which are involved in the formationof L¹ linkages between the drug and the linker: —NH₂, —NHR¹, —CONHR¹,—O—C(═O)NHR¹, —SO₂NHR¹, —OSO₂NHR¹, —NR¹C(═O)NHR¹ or —N(R¹)SO₂NHR¹; L² isO; E is bond; L¹ is linkages selected from the group consisting of:

wherein, X is independently a bond, O or NR¹, Y is C═O or SO₂, A and A¹are CH₂—CH₂, B is S—S, a is 0 and D² is NO₂.

An embodiment of the present invention is the compound of formula (I),wherein D¹ is a hydroxyl or sulfahydryl containing drug molecule such asDrug-OH or Drug-SH, wherein functional groups OH and SH are involved inthe formation of L¹ linkages between the drug and the linker; L² is O; Eis bond, L¹ is a linkage selected from the group consisting of:

wherein, X is independently a bond, O or NR¹, R¹ is not a bond, Y is C═Oor SO₂, A and A¹ are CH₂CH₂; B is S—S; a is 0; and D² is NO₂.

An embodiment of the present invention is the compound of formula (I),wherein D¹ is a drug molecule having carboxyl (—CO₂H) as a reactivefunctional group such as —CO₂H which is involved in the formation of L¹linkages between the drug and the linker; L² is O; E is bond; L¹ is O orNR¹ or a linkage selected from the group consisting of:

wherein, X is independently a bond, O or NR¹, R¹ is not a bond; Y is C═Oor SO₂; A and A¹ are CH₂CH₂; B is S—S; a is 0 and D² is NO₂.

Another embodiment of the present invention is the compounds of formula(I), wherein D¹ is an antioxidant or free radical scavenger such as ahydroxyl-containing stable radical such a4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (4-hydroxy-TEMPO),4-carboxy-2,2,6,6-tetramethylpiperidin-1-oxyl (4-carboxy-TEMPO) or anyother amino-/carboxyl-/hydroxyl-containing antioxidants or radical/superoxide scavengers, and D² is NO₂. Theamino-/carboxyl-/hydroxyl-containing antioxidants and radical/superoxide scavengers can be known or investigational.

An embodiment of the present invention is the compound of formula (I),wherein L¹ is

wherein, X is a bond, O, S or NR¹; L² is O, E is a bond; A and A¹ areCH₂CH₂; B is S—S; a is 0; and D² is NO₂.

An embodiment of the present invention is the compounds of formula (I),wherein D¹ and L¹ are as defined above; L² is O; A is 1,2-phenylene,1,3-phenylene, or 1,4-phenylene; A¹ is CH₂; E is CH₂; B is S—S; a is 0and D² is NO₂.

An embodiment of the present invention is the compounds of formula (I),wherein L² is O; A and A¹ are CH₂; E is CH₂; B is a bond or (CH₂)_(b); bis 1-6; a is 0; D² is NO₂ and L¹ is a group selected from

wherein, X is O, S or NR¹; R¹ is as defined.

An embodiment of the invention is the compound of formula I selectedfrom the groups consisting of:

A. Prodrugs:

(a) From Carboxyl-Containing Drugs:

(b) From Amino-Containing Drugs:

(c) From Hydroxyl-Containing Drugs:

-   -   Y═O, NR¹ (R¹=H, Alkyl, Aralkyl, Cycloalkyl), (CH₂)_(n)C(═O)        (n=1-6), (CH₂)_(n)CO₂ ⁻    -   Z═C═O, SO₂, P(═O)YR³ (R³=H or a metal ion)    -   R²═H, a bond, CH₂CH₂N(CH₃)₂, HCl, an Amino acid, or any molecule        containing solubilizing groups such as carboxylic acid,        sulphonic acid, hydroxyl, amino groups, polyethyleneglycol        (PEG), a metal ion such a Na⁺, Ca²⁺, etc.        B. NO-Releasing Prodrugs

(a) From Carboxyl-Containing Drugs

(b) From Amino-Containing Drugs

(c) From Hydroxyl-Containing Drugs

C. Mutual or Double Prodrugs(a) From Two Amino-Containing Drugs

(b) From Two Carboxyl-Containing Drugs

(c) From Two Hydroxyl-Containing Drugs

(d) From an Amino-Containing Drug and a Carboxyl-Containing Drug:

(e) Mutual Prodrugs of One Carboxyl-Containing and OneHydroxyl-Containing Drugs

(f) Mutual Prodrugs of One Amino-Containing and One Hydroxyl-ContainingDrugs

An embodiment of the invention is a pharmaceutical compositioncomprising a therapeutically effective amount of the compound of formulaI, or a pharmaceutical salt thereof and one or more pharmaceuticallyacceptable carriers, vehicles or diluents.

Another embodiment of the invention is a pharmaceutical compositioncomprising a therapeutically effective amount of the compound of formulaI selected from the group consisting of I-C1-PD1, I-C1-PD2, I-C1-PD3,I-C1-PD4, I-C1-PD4a, I-C1-PD4b, I-C1-PD5, I-C1-PD6, I-C1-PD7, I-C1-PD8,I-C1-PD9, I-C1-PD10, I-C1-PD11, I-C1-PD12, I-C1-PD13, I-C1-PD14,I-C1-PD15a, I-C1-PD15b, 1-A1-PD1, I-A1-PD2, I-A1-PD3, I-A1-PD4,I-A1-PD5, I-A1-PD6, I-A1-PD7, I-A1-PD8, I-A1-PD9, I-A1-PD10, I-A1-PD11,I-A1-PD12, I-A1-PD13, I-A1-PD14, I-A1-PD15A, I-A1-PD15Aa, I-A1-PD15B,I-A1-PD15Bb, I-A1-PD16, I-A1-PD17, I-A2-PD1, I-A2-PD2, I-A2-PD2b,I-A2-PD3a, I-A2-PD3b, 1-A2-PD4, I-A2-PD5, I-A3-PD1, I-A3-PD2a,I-A3-PD2b, I-A3-PD3a, I-A3-PD3b, 1-A3-PD4, I-A3-PD5, I-A3-PD6,I-A3-PD7b, I-H1-PD1, I-H1-PD2, I-H1-PD3, I-H1-PD4, I-H1-PD5, I-H1-PD6,I-H1-PD7, I-H1-PD8, I-H1-PD9, I-H1-PD10, I-H1-PD11, I-H1-PD12,I-H1-PD13, I-Taxol-PD1, I-Taxol-PD2, I-Taxol-PD3, I-Taxol-PD4,I-Taxol-PD5, I-Taxol-PD6, I-S23-PD1, I-C1-NOPD1, I-C1-NOPD2,I-C1-NOPD3a, I-C1-NOPD3b, I-C1-NOPD4, I-C1-NOPD5a, I-C1-NOPD5b,I-C1-NOPD6, I-C1-NOPD7, I-C1-NOPD8a, I-C1-NOPD8b, I-C1-NOPD9,I-C1-NOPD10, I-C1-NOPD11a, I-C1-NOPD13, I-C1-NOPD14a, I-C1-NOPD14b,I-C1-NOPD15b, I-C1-NOPD16, I-C1-NOPD17a, I-C1-NOPD17b, I-C1-NOPD18,I-C1-NOPD19, I-C1-NOPD20a, I-C1-NOPD20b, I-C1-NOPD21, I-C1-NOPD22,I-C1-NOPD23b, I-C1-NOPD24, I-C1-NOPD25, I-C1-NOPD26, I-A1-NOPD1,I-A1-NOPD2, I-A1-NOPD3A, I-A1-NOPD3B, I-A1-NOPD4, I-A1-NOPD5,I-A1-NOPD6, I-A1-NOPD7, I-A1-NOPD8, I-A1-NOPD9, I-A1-NOPD10a,I-A1-NOPD10b, I-A2-NOPD1a, I-A2-NOPD1b, I-A2-NOPD2a, I-A2-NOPD2b,I-A3-NOPD1a, I-A3-NOPD1b, I-A3-NOPD2a, I-A3-NOPD2b, I-H1-NOPD1,I-H1-NOPD2a, I-H1-NOPD2b, I-H1-NOPD3, I-H1-NOPD4, I-H1-NOPD5b,I-H1-NOPD6, I-H1-NOPD7, I-H1-NOPD8, I-H1-NOPD9, I-H1-NOPD10, I-AA-MPD1,I-AA-MPD2, I-AA-MPD3a, I-AA-MPD4, I-AA-MPD5, I-AA-MPD6, I-AA-MPD7,I-AA-MPD8, I-AA-MPD9, I-AA-MPD10, I-AA-MPD11, I-AA-MPD12, I-AA-MPD13,I-AA-MPD14, I-AA-MPD15, I-AA-MPD16, I-AA-MPD17, I-AA-MPD18, I-AA-MPD19,I-AA-MPD20, I-AA-MPD21, I-AA-MPD22, I-AA-MPD23, I-AA-MPD24, I-AA-MPD25,I-AA-MPD26, I-AA-MPD27, I-CC-MPD1, I-CC-MPD2, I-CC-MPD3, I-CC-MPD4,I-CC-MPD5, I-CC-MPD6, I-HH-MPD1, I-HH-MPD2, I-HH-MPD3, I-HH-MPD4,I-HH-MPD5, I-HH-MPD6, I-HH-MPD7, I-HH-MPD8, I-HH-MPD9, I-HH-MPD10,I-HH-MPD11, I-HH-MPD12, I-HH-MPD13, I-HH-MPD14, I-HH-MPD15, I-HH-MPD16,I-HH-MPD17, I-HH-MPD18, I-HHAH-TMPD1, I-CA-MPD1, I-CA-MPD2, I-CA-MPD3,I-CA-MPD4, I-CA-MPD5, I-CA-MPD6, I-CA-MPD7, I-CA-MPD8, I-CA-MPD9,I-CA-MPD10, I-CA-MPD11, I-CA-MPD12, I-CA-MPD13, I-CA-MPD14, I-CA-MPD15,I-CA-MPD16, I-CA-MPD17, I-CA-MPD18, I-CA-MPD19, I-CA-MPD20, I-CA-MPD21,I-CA-MPD22, I-CA-MPD23, I-CA-MPD24, I-CA-MPD25, I-CA-MPD26, I-CA-MPD27,I-CA-MPD28, I-CA-MPD29, I-CA-MPD30, I-AH-MPD1, I-AH-MPD2, I-AH-MPD3,I-AH-MPD4, I-AH-MPD5, I-AH-MPD6, I-AH-MPD7, I-AH-MPD8, I-AH-MPD9,I-AH-MPD10, I-AH-MPD11, I-AH-MPD12, I-AH-MPD13, I-AH-MPD14, I-AH-MPD15,I-AH-MPD16, I-AH-MPD17, I-AH-MPD18, I-AH-MPD19, I-AH-MPD20, I-AH-MPD21,I-AH-MPD22, I-AH-MPD23, I-AH-MPD24, I-AH-MPD25, I-AH-MPD26, I-CH-MPD1,I-CH-MPD2, I-CH-MPD3, I-CH-MPD4, I-CH-MPD5, and I-CH-MPD6 or apharmaceutical salt thereof and one or more pharmaceutically acceptablecarriers, vehicles or diluents.

An embodiment of the invention is a method of treating a mammal or humanin need thereof comprising administering a therapeutically effectiveamount of the pharmaceutical composition comprising the compound offormula I.

Another embodiment of the invention is the below listed novelintermediates:

Another embodiment of the invention is use of the above listed novelintermediates in the processes for the preparation of compounds offormula I.

Further embodiments include methods of preparation and methods of use ofcompounds of formula (I) or pharmaceutically acceptable salts thereof.

Another embodiment of the invention is process for the preparation ofcompounds of formula I, or pharmaceutically acceptable salts thereof,wherein the process comprises of:

monoprotection of Bis-(2-hydroxyethyl)disulphide (SL-1) with anappropriate hydroxyl protecting group to give a correspondingmonoprotected intermediate,

conversion of the corresponding monoprotected intermediate to anactivated formyl intermediate by treating with phosgene or itsequivalent, and

reaction of the activated formyl intermediate with an appropriate amino-or hydroxy containing D¹ to give the corresponding compound of formulaI.

Another embodiment of the invention is a process for the preparation ofcompounds of formula I, or pharmaceutically acceptable salts thereof,wherein the process comprises of:

converting carboxy containing D1 into an activated intermediatecomprising acyl halide, imidazolide or isocyanate, and

reacting the activated intermediate with a linker intermediate to obtainthe compound of formula I.

In another embodiment, the invention is a process in which themonoprotected intermediate is LI1x, and the activated formylintermediate is LI1xy.

Another embodiment of the invention is a process for preparation ofcompounds of formula (I), wherein D₂ is NO₂ or pharmaceuticallyacceptable salts thereof, wherein the process comprises, mixing aselectively protected and activated. D1 with a solution of2-((2-hydroxyethyl)dithio)ethyl nitrate (LI-2b) in a suitable solvent inpresence of a suitable coupling agent.

Another embodiment of the invention is a process for preparation ofcompounds of formula (I), wherein D² is NO₂ or pharmaceuticallyacceptable salts thereof, wherein a process comprises, converting2-((2-hydroxyethyl)dithio)ethyl nitrate (LI-2b) into its formyl halideor imidazolide (LI-4x) by using a phosgene or its equivalent reagent andmixing/reacting the resulting reactive intermediate with a suitableamino- or hydroxy-containing drug in suitable solvent in presence of asuitable base.

Another embodiment of the invention is a process for preparation ofcompounds of formula (I), wherein D² is NO₂ or pharmaceuticallyacceptable salt thereof, wherein the process comprises, mixing/reactinga selectively protected and activated drug with a solution of2-((2-aminoethyl)dithio)ethyl nitrate (LI-5) in a suitable solvent inpresence of a suitable coupling agent and/or base.

Another embodiment of the invention is a process for preparation ofmutual prodrugs of compounds of formula (I), or pharmaceuticallyacceptable salts thereof, wherein a process comprises,

A) monoprotection of Bis-(2-hydroxyethyl)disulphide (SL-1) with anappropriate hydroxyl protecting group to give the correspondingmonoprotected intermediate LI-1x,

B) reaction of formyl linker intermediate LI-1xy with amino or hydroxylcontaining drug (D¹) to obtain the prodrug of formula I with freehydroxyl group on the linker,

C) conversion of the intermediate obtained in the step B into activatedformyl halide or imidazolide derivative, and

D) reaction of the intermediate obtained in the step C with the drug D²to obtain the mutual prodrug of formula I.

Further embodiments of the invention are processes for the preparationof compounds of formula I, or pharmaceutically acceptable salts thereof,wherein the processes comprise of the steps that are generally depictedin the schemes 1-23.

Further embodiments include the pharmaceutical composition comprising atherapeutically effective amount of novel intermediates or apharmaceutically acceptable salt thereof and one or morepharmaceutically acceptable carriers, vehicles or diluents.

Another embodiment of the invention is use of compounds of formula (I)or pharmaceutically acceptable salt thereof, in the treatment of diseaseconditions originally treatable by the corresponding free drug(s).

It should be understood that while this invention has been describedherein in terms of specific embodiments set forth in detail, suchembodiments are presented by way of illustration of the generalprinciples of the invention, and the invention is not necessarilylimited thereto. Certain modifications and variations in any givenmaterial, process step or chemical formula will be readily apparent tothose skilled in the art without departing from the true spirit andscope of the present invention, and all such modifications andvariations should be considered within the scope of the claims thatfollow. The contents of the articles, patents, and patent applications,and all other documents mentioned or cited herein, are herebyincorporated by reference in their entirety to the same extent as ifeach individual publication was specifically and individually indicatedto be incorporated by reference.

Yet another embodiment of the invention is a compound of formula Icontaining an amino-containing therapeutic agent selected from the groupconsisting of: I-AA-MPD1, I-AA-MPD2, I-AA-MPD3, and I-AA-MPD4.

Another embodiment of the invention is double prodrug of formula (I)selected from the group consisting of: I-AA-MPD5, I-AA-MPD6, I-AA-MPD7,and I-AA-MPD8.

The present invention also provides mutual prodrugs of formula (I)selected from the group consisting of: I-CA-MPD1, I-CA-MPD2, I-CA-MPD3,I-CA-MPD4, I-CA-MPD5, I-CA-MPD6, I-CA-MPD7, I-CA-MPD8, I-CA-MPD9,I-CA-MPD10, I-CA-MPD11, I-CA-MPD12, I-CA-MPD13, I-CA-MPD14, I-CA-MPD15,I-CA-MPD16, I-CA-MPD17, I-CA-MPD18, I-CA-MPD19, I-CA-MPD20, I-CA-MPD21,I-CA-MPD22, I-CA-MPD23, I-CA-MPD24, I-CA-MPD25, I-CA-MPD26, I-CA-MPD27,I-CA-MPD28, I-CA-MPD29, and I-CA-MPD30.

In another embodiment, the invention provides compounds of formula (I)selected from the group of mutual prodrugs made from amino-containingtherapeutic agent and a hydroxyl-containing therapeutic agent such as:I-AH-MPD1, I-AH-MPD2, I-AH-MPD3, I-AH-MPD4, I-AH-MPD5, I-AH-MPD6,I-AH-MPD7, I-AH-MPD8, I-AH-MPD9, I-AH-MPD10, I-AH-MPD11, I-AH-MPD12,I-AH-MPD13, I-AH-MPD14, I-AH-MPD15, I-AH-MPD16, I-AH-MPD17, I-AH-MPD18,I-AH-MPD19, I-AH-MPD20, I-AH-MPD21, I-AH-MPD22, I-AH-MPD23, I-AH-MPD24,I-AH-MPD25, and I-AH-MPD26.

Yet another embodiment of the invention relates to compounds of formula(I) of mutual prodrugs made from a hydroxyl-containing therapeutic agentand a hydroxyl-containing therapeutic agent such as: I-HH-MPD1,I-HH-MPD2, I-HH-MPD3, I-HH-MPD4, I-HH-MPD5, I-HH-MPD6, I-HH-MPD7,I-HH-MPD8, I-HH-MPD9, I-HH-MPD10, I-HH-MPD11, I-HH-MPD12, I-HH-MPD13,I-HH-MPD14, I-HH-MPD15, I-HH-MPD16, I-HH-MPD17, and I-HH-MPD18.

The present invention also provides compounds of formula (I) containingwater-soluble prodrugs of insoluble or sparingly-soluble therapeuticagents such as: I-H1-PD1, I-H1-PD2, I-H1-PD3, I-H1-PD4, I-H1-PD5,I-H1-PD6, I-H1-PD7, I-H1-PD8, I-H1-PD9, I-H1-PD10, I-H1-PD11, I-H1-PD12,I-H1-PD13, I-A1-PD1, I-A1-PD2, I-A1-PD3, I-A1-PD4, I-A1-PD5, I-A1-PD6,I-A1-PD7, I-A1-PD8, I-A1-PD9, I-A1-PD10, I-A1-PD11, I-A1-PD12,I-A1-PD13, I-A1-PD14, I-A1-PD15A, I-A1-PD1Aa, I-A1-PD15B, I-A1-PD15Bb,I-A1-PD16, I-A1-PD17, I-A2-PD1, I-A2-PD2, I-A2-PD2b, I-A2-PD3a,I-A2-PD3b, I-A2-PD4, I-A2-PD5, I-A3-PD1, I-A3-PD2a, I-A3-PD2b,I-A3-PD3a, I-A3-PD3b, I-A3-PD4, I-A3-PD5, I-A3-PD6, I-A3-PD7b, I-H1-PD1,I-H1-PD2, I-H1-PD3, I-H1-PD4, I-H1-PD5, I-H1-PD6, I-H1-PD7, I-H1-PD8,I-H1-PD9, I-H1-PD10, I-H1-PD11, I-H1-PD12, I-H1-PD13, I-Taxol-PD1,I-Taxol-PD2, I-Taxol-PD3, I-Taxol-PD4, I-Taxol-PD5, I-Taxol-PD6, andI-S23-PD1.

Another embodiment of the invention relates to the compounds of formula(I), selected from the group of NO-releasing prodrugs consisting of:I-C1-NOPD1, I-C1-NOPD2, I-C1-NOPD3a, I-C1-NOPD3b, I-C1-NOPD4,I-C1-NOPD5a, I-C1-NOPD5b, I-C1-NOPD6, I-C1-NOPD7, I-C1-NOPD8a,I-C1-NOPD8b, I-C1-NOPD9, I-C1-NOPD10, I-C1-NOPD11a, I-C1-NOPD13,I-C1-NOPD14a, I-C1-NOPD14b, I-C1-NOPD15b, I-C1-NOPD16, I-C1-NOPD17a,I-C1-NOPD17b, I-C1-NOPD18, I-C1-NOPD19, I-C1-NOPD20a, I-C1-NOPD20b,1-C1-NOPD21, I-C1-NOPD22, I-C1-NOPD23b, I-C1-NOPD24, I-C1-NOPD25,I-C1-NOPD26, I-A1-NOPD1, I-A1-NOPD2, I-A1-NOPD3A, I-A1-NOPD3B,I-A1-NOPD4, I-A1-NOPD5, I-A1-NOPD6, I-A1-NOPD7, I-A1-NOPD8, I-A1-NOPD9,I-A1-NOPD10a, I-A1-NOPD10b, I-A2-NOPD1a, I-A2-NOPD1b, I-A2-NOPD2a,I-A2-NOPD2b, I-A3-NOPD1a, I-A3-NOPD1b, I-A3-NOPD2a, I-A3-NOPD2b,I-H1-NOPD1, I-H1-NOPD2a, I-H1-NOPD2b, I-H1-NOPD3, I-H1-NOPD4,I-H1-NOPD5b, I-H1-NOPD6, I-H1-NOPD7, I-H1-NOPD8, I-H1-NOPD9,I-H1-NOPD10.

Another aspect of the invention provides the use of the compounds offormula (I) in combination with a compound used to treat cardiovasculardiseases selected from the group consisting of: beta adrenergicblockers, calcium channel blockers, angiotensin II receptor antagonists,antithrombotics, HMGCoA reductase inhibitors, aspirin or nitrooxyderivatives of aspirin, nitrosated beta blockers, nitrosated ornitrosilated calcium channel blockers. Suitable drugs are described inthe literature such as the Merck Index, IDdb, Prous Science'sIntegrity®, Prous Science Drugs of the Future™, The Ensemble® and thelike.

Another aspect of the invention provides the use of the pharmaceuticalcompositions containing compounds of formula (I) in combination with acompound, used to treat other diseases such as cardiovascular diseases,selected from beta adrenergic blockers, calcium channel blockers,angiotensin II receptor antagonists, antithrombotics, HMGCoA reductaseinhibitors, aspirin or nitrooxy derivatives of aspirin, nitrosated betablockers, nitrosated or nitrosilated calcium channel blockers.Pharmaceutical compositions containing two or more of compounds of theinvention can be used for the purpose of combination therapy. Thesepairs of compounds of invention can be from the same therapeutic area orfrom different therapeutic areas for treating one or more diseases orconditions.

The compounds of the invention, which have one or more asymmetric carbonatoms, can exist as the optically pure enantiomers, pure diastereomers,enantiomer racemic mixtures, diastereomer racemic mixtures, racemates orracemate mixtures. Within the scope of the invention are also all thepossible isomers, stereoisomers and their mixtures of the compounds offormula (I).

Another embodiment of the invention relates to the pharmaceuticalcomposition comprising one or more compounds of formula (I) orpharmaceutically acceptable salts thereof and one or morepharmaceutically acceptable carriers, vehicles or diluents.

Another embodiment of the invention relates to the pharmaceuticalcomposition comprising one or more compounds of formula (I) orpharmaceutically acceptable salts thereof and at least anotherpharmaceutically active compound. The pharmaceutically active compoundcan be from the same or different therapeutic areas for treating one ormore disease condition(s) together with one or more pharmaceuticallyacceptable carriers, vehicles or diluents.

Further embodiments include methods of use of compounds of formula (I)or pharmaceutically acceptable salts thereof.

Another embodiment of the invention is a process for preparation ofcompounds of formula (I) or pharmaceutically acceptable salts thereof,wherein the process comprises, mixing a selectively protected andactivated drug with a solution of 2-((2-hydroxyethyl)dithio)ethylnitrate in a suitable solvent in presence of a suitable coupling agent.Another embodiment of the invention is a compound or intermediategenerated in the above methods and processes.

Another embodiment of the invention is a process for preparation ofcompounds of formula (I) or pharmaceutically acceptable salts thereof,wherein a process comprises, converting 2-((2-hydroxyethyl)dithio)ethylnitrate into its formyl halide or imidazolide by using a phosgene or itsequivalent reagent and mixing/reacting the resulting reactiveintermediate with a suitable drug in suitable solvent in presence of asuitable base.

Another embodiment of the invention is a process for preparation ofcompounds of formula (I) or pharmaceutically acceptable salt thereof,wherein the process comprises, mixing/reacting a selectively protectedand activated drug with a solution of 2-((2-aminoethyl)dithio)ethylnitrate (or its acid salt) in a suitable solvent in presence of asuitable coupling agent and/or base.

Another embodiment of the invention comprises the novel intermediatesformed in the preparation of present invention. Further embodimentsinclude a pharmaceutical composition comprising a therapeuticallyeffective amount of novel intermediates or a pharmaceutically acceptablesalt thereof and one or more pharmaceutically acceptable carriers,vehicles or diluents.

Another embodiment of the invention is processes for the preparation ofcompounds of formula (I) or pharmaceutically acceptable salt thereof, aswell as the starting materials and intermediates involved as depicted inschemes 1-23.

Another embodiment of the invention the novel intermediates obtained inthe preparation of compounds of formula I, wherein the intermediates areselected from:

Another embodiment of the invention is use of compounds of formula (I)or pharmaceutically acceptable salts thereof, in the treatment ofdisease conditions originally treatable by the corresponding free drugs.

Another embodiment of the invention includes but not limited to apharmaceutical composition comprising the compounds of formula (I), orpharmaceutically acceptable salts thereof, selected from the group ofNO-releasing prodrugs described herein, and one or more pharmaceuticallyacceptable carriers, vehicles or diluents.

It should be understood that while this invention has been describedherein in terms of specific embodiments set forth in detail, suchembodiments are presented by way of illustration of the generalprinciples of the invention, and the invention is not necessarilylimited thereto. Certain modifications and variations in any givenmaterial, process step or chemical formula will be readily apparent tothose skilled in the art without departing from the true spirit andscope of the present invention, and all such modifications andvariations should be considered within the scope of the claims thatfollow. The contents of the articles, patents, and patent applications,and all other documents mentioned or cited herein, are herebyincorporated by reference in their entirety to the same extent as ifeach individual publication was specifically and individually indicatedto be incorporated by reference.

Potential Examples of Mutual Prodrugs/Codrugs

Mutual prodrugs made from an amino-containing therapeutic agent andanother amino-containing therapeutic agent:

A Mutual Prodrug of desloratadine and pseudoephedrine (I-AA-MPD1) isproposed as a potential treatment option for seasonal allergic rhinitis(SAR). Desloratadine (an active metabolite of loratadine) is a new,non-sedating, long-acting histamine antagonist and has been showneffective in the treatment of nasal and non-nasal symptoms associatedwith SAR. Pseudoephedrine is an oral decongestant.

A Mutual Prodrug of amlodipine (Pfizer's Norvasc®) and lisinopril(Zeneca's Zestril®) (I-AA-MPD2) is proposed as a potential treatmentoption for hypertension and congestive heart failure. Amlodipine is acalcium channel blocker and is used as an antihypertensive andantianginal agent. Lisinopril is an angiotensin-converting enzyme (ACE)inhibitor and is used for the treatment of hypertension and congestiveheart failure. A combination therapy using these two drugs has beenproven to be more effective treatment option than monotherapy usingeither of these drugs.

A Mutual Prodrug of amlodipine (Pfizer's Norvasc®) and losartan (Merck'sCozaar®) (I-AA-MPD3a) is proposed as a potential treatment option formild to moderate hypertension. Amlodipine is a calcium channel blockerand is used as an antihypertensive and antianginal agent. Losartanpotassium is an angiotensin II blocker and is used for the treatment ofhypertension. A combination therapy using these two drugs has beenproven to be more effective treatment option than monotherapy usingeither of these drugs.

Examples of mutual prodrugs and double prodrugs of valdecoxib andcelecoxib containing a disulfide linker are: I-AA-MPD4 and I-AA-MPD5.

Examples of double prodrugs of valdecoxib or celecoxib containingnon-disulfide linkers: I-AA-MPD6, I-AA-MPD7, I-AA-MPD8.

A Mutual Prodrug of fluoxetine (Lilly's Prozac®) and olanzapine (Lilly'sZyprexa®) (I-AA-MPD9) is proposed for potential treatment of patientswith Bipolar disorder. Fluoxetine and Olanzapine are used in combinationto treat patients with bipolar disorder while being spared thetreatment-emergent mania that such patients often get on antidepressantmonotherapy.

Example of double prodrug of gabapentin is proposed as potentialantiepileptic agent: I-AA-MPD10.

Mutual Prodrugs Made from an Amino-Containing Therapeutic Agent and aCarboxyl-Containing Therapeutic Agent:

A mutual prodrug of cetirizine and pseudoephedrine (I-CA-MPD1) isproposed for treatment of rhinitis. Cetirizine is an antihistamine andpseudoephedrine is a nasal decongestant.

Mutual prodrugs of gabapentin and valproic acid are potentialantiepileptic agents. This same kind of prodrug may be a potentialtreatment option for patients with bipolar disorder and other mentalillnesses. The following are some of the examples:

Other illustrative examples of mutual prodrugs under this categoryinclude the following: Mutual prodrugs of valproic acid and othercarboxyl-, hydroxyl-, and amino-containing (including amide-, andsulfonamide-containing) anticonvulsant agents such as levetiracetam,lamotrigine, pregabalin, carbamazepine, oxcarbamazepine, licarbazepine,felbamate, topiramate and the like. (Structures are given below). Thelist also includes investigational antiepileptic agents such asantipamezole, licarbazepine, Eslicarbazepine Acetate (BIA 2-093),fluorofelbamate, isovaleramide (NPS 1776), retigabine (D-23129),safinamide (NW-1015), stiripentol (STP), talampanel (TLP),(2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide 83alpha (ucb34714), valrocemide (TV 1901), and the like.

Mutual Prodrugs can be made from combination of any two anti-convulsantagents listed above or any other suitable anticonvulsant agents.

Mutual prodrug of gabapentin and naproxen (I-CA-MPD22) is proposed forpotential treatment option for neurological pain and inflammation.

Mutual Prodrugs Made from an Amino-Containing Therapeutic Agent and aHydroxyl-Containing Therapeutic Agent:

Mutual prodrugs of norfloxacin and metronidazole (I-AH-MPD1, I-AH-MPD2,I-AH-MPD3) are proposed for potential treatment of diarrhea anddysentery of bacterial, amoebic and mixed origin. Metronidazole is anantianaerobic agent and used in combination with antibiotics such asnorfloxacin, ciprofloxacin, etc. for the treatment of patients withdiarrhea and dysentery of bacterial, amoebic and mixed origin.

A mutual prodrug of loperamide and norflaxacin (I-AH-MPD4) is proposedfor potential treatment of diarrhea and dysentery.

A mutual prodrug of valdecoxib and tramadol (I-AH-MPD5 and I-AH-MPD6) asa potential therapy in postoperative pain management.

A mutual prodrug of gabapentin and tramadol (I-AH-MPD7) is proposed forpotential treatment of neuropathic pain after spinal cord injury.

A mutual prodrug of venlafaxine and paroxetine (I-AH-MPD8) is proposedfor potential treatment of neurological and depression relateddisorders.

Mutual Prodrugs Made from a Hydroxyl-Containing Therapeutic Agent andAnother Hydroxyl-Containing Therapeutic Agent:

Mutual prodrugs of zidovudine (AZT/Retrovir) and lamivudine (3TC/Epivir)(I-HH-MPD1, I-HH-MPD2) are proposed as a potential treatment option forHIV and other viral infections.

Potential Examples of Water-Soluble Prodrugs

Water-soluble prodrugs of insoluble/sparingly-soluble therapeutic agentscan be prepared using the same linker technology.

Water-soluble prodrugs of metronidazole include: I-H1-PD-2, I-H1-PD-3,I-H1-PD-4.

Water-soluble prodrugs of valdecoxib include: I-A3-PD1, I-A3-PD2a,I-A3-PD2b, I-A3-PD3a, I-A3-PD3b, I-A3-PD4, I-A3-PD5, I-A3-PD6, andI-A3-PD7b.

Water-soluble prodrugs of paclitaxel include: I-Taxol-PD1,I-Taxol-PD2,1-Taxol-PD3, I-Taxol-PD4, I-Taxol-PD5, I-Taxol-PD6, andI-S23-PD1.

Potential Examples of NO-Releasing Prodrugs

In the following potential examples, X is O, NR¹ (R¹=H, alkyl) or abond; Y is CO, SO₂, P(═O)XR¹ or bond; R¹ is H, alkyl, aralkyl, or ametal ion; A is a bond, 1,4-/1,3-/1,2-phenylene or (CH₂)_(o) (o=0-6) andm is 1-2 unless otherwise stated;

Prodrugs of Valproic Acid (Anticonvulsant):

Drugs Containing Reactive Primary and Secondary Amines, Amide-NH,Urea-NH, Sulfonamide-NH, Sulfamate-NH, and Carbamate-NH:

NO-Releasing Prodrugs of Paracetamol/Acetaminophen (Analgesic andAntipyretic):

Additional Potential Examples

In the following additional potential examples, X is O, NR¹ (R¹=H,alkyl) or a bond; Y is CO, SO₂, P(═O)XR¹ or bond; R¹ is H, alkyl,aralkyl, or a metal ion; A is a bond, 1,4-/1,3-/1,2-phenylene or(CH₂)_(o) (o=0-6) and m is 1-2 unless otherwise stated;

NO-Releasing Prodrugs of Nicotinamide:

NO-Releasing Prodrugs of NSAIDs:NO-Releasing Prodrugs of Aspirin

NO-Releasing Prodrugs of Paracetamol

NO-Releasing Prodrugs of Mesalamine

NO-Releasing Prodrugs of Naproxen

NO-Releasing Prodrugs of Flurbiprofen

NO-Releasing Prodrugs of Sulindac

NO-Releasing Prodrugs of Ketoprofen

NO-Releasing Prodrugs of Indomethacin

NO-Releasing Prodrugs of Ibuprofene

NO-Releasing Prodrugs of Ketorolac

NO-Releasing Prodrugs of Diclofenac

NO-Releasing Prodrugs of Glucocorticoids:NO-Releasing Prodrug of Prednisolone

NO-Releasing Prodrug of Ursodeoxycholic Acid

NO-Releasing Prodrug of Hydrocortisone

NO-Releasing Prodrug of Budesonide

NO-Releasing Prodrugs of Antioxidants and for Free Radical Scavengers:NO-Releasing Prodrug of TEMPOL (4-Hydroxy-TEMPO):

NO-Releasing Prodrugs of Probucol and AGI-1067:

NO-Releasing Prodrugs of Lipoic Acid:

NO-Releasing Prodrugs of Vitamin E (Alfa-Tocopherol):

NO-Releasing Prodrugs of Edaravone (3-Methyl-1-Phenyl-2-Pyrazolin-5One):

NO-Releasing Prodrugs of Antibiotics:NO-Releasing Prodrugs of Metronidazole

NO-Releasing Prodrugs of Norfloxacin:

NO-Releasing Prodrugs of Antiepileptic Agents:NO-Releasing Prodrugs of Valproic Acid

NO-Releasing Prodrug of Gabapentin

NO-Releasing Prodrug of Levetiracetam

NO-Releasing Prodrug of Lamotrigine

NO-Releasing Prodrug of Carbamazepine

Plausible Mechanisms of Drug Release from Prodrugs

Drugs can be released from the prodrugs and mutual prodrugs via cleavageof bio-labile linker(s) in vivo (cleavage can be either chemical orenzymatic or both) by illustrative mechanisms as shown in Schemes M1through M5.

Plausible mechanisms for concomitant release of nitric oxide (NO) andfree drug from NO-releasing prodrug(s) of amino-, hydroxyl-, orcarboxyl-containing drug(s) are illustratively shown in Scheme M1. Thus,the attack of thiolate ion (from GSH or any other sulfahydryl-containingspecies) on nitrooxy-containing prodrug would release carboxylicacid-containing free drug, episulfide (d) and the intermediate conjugate(a) according to path 1. If the prodrugs are made from amino-, orhydroxyl-containing drugs, then the prodrug would be cleaved via path 2to release the corresponding free drug, the cyclic thiocarbonateintermediate (c) and the intermediate conjugate (a). The cyclicthiocarbonate intermediate may further breakdown into episulfide (d) andcarbon dioxide. The reactive episulfide (d) would be further neutralizedby glutathione. The nitrate ester-containing intermediate conjugate canfurther break down in the presence of GSH to glutathione dimer (GS-SG)and transient intermediate (b), which can break down via path 3 torelease NO. It is also possible the same transient intermediate canbreak down via path 4 to yield episulfide (d) and a relatively innocuousnitrate anion (NO₃ ⁻).

Plausible mechanisms of drug release from mutual prodrugs of onecarboxyl-containing and one amino-/hydroxyl-containing drug is shown inScheme M2.

Plausible mechanism of drug release from prodrugs (including mutual andNO-releasing prodrugs of amino-, hydroxyl- and carboxyl-containingdrugs) containing modified bio-labile linkers is shown in Scheme M3.Thus, the thiolate anion derived from the attack of glutathione ondisulfide of the prodrug may trigger cyclization to release the freedrug (D1-X^(m1)H) and a stable six-membered (or five-membered, if X^(m2)is a bond) thio-lactone intermediate.

Plausible mechanisms of drug release from double/mutual prodrugscontaining additional linkages to couple two hydroxyl-containing drugsare shown in Scheme M4. Thus, the thiolate anion generated by the attackof glutathione on disulfide bond of the prodrug triggers furthercleavage as shown to release the free drug (D¹-OH) and a five-membered2-imidazolidone. Through in vitro decomposition studies, we have foundthat the drug release from this type of prodrug is more facile when Rgroup is an alkyl group.

This invention also covers novel bio-labile linkers containing1,4-phenylene group and 1,2-phenylene group as shown in Schemes 5 and 6,respectively. As depicted in Scheme M5, the linker is expected torelease the free Drug¹ upon glutathione-assisted cleavage and maygenerate 1,4-quinonemethid (ea) as a byproduct via 1,6-eliminationprocess. Similarly, the free Drug² is expected to be released from theintermediate conjugate (a) as shown in the scheme.

As depicted in Scheme M6, the 1,2-phenylene-containing linker is alsoexpected to release free drugs upon glutathione assisted cleavage andgenerate 1,2-quinonemethid (eb) as a byproduct via 1,4-eliminationprocess (via pathway ‘b’). However, this linker can also cleave viapathway ‘a’ to generate benzo-monothiocarbonate as a byproduct. Althoughthe generated byproducts seem to be toxic, they are likely to be quicklyneutralized by detoxification enzymes in the body.

Diazepam, a benzodiazepine tranquilizer, is very sparingly water-solubledrug and a water-soluble acyclic prodrug of diazepam can be made byusing our linker technology. As shown in the Scheme M7, reduction ofdisulfide bond in the prodrug triggers release of open-chainintermediate of diazepam which spontaneously cyclizes to diazepam invivo.

Where GSH is glutathione (reduced) or any other in vivo bioreductiveagent that can reduce the disulfide bond. As illustrated, cleavage ofdisulfide bond triggers further breakage of the remaining portion of thelinker to release the free drugs. In the process, some byproducts aregenerated and these are either eliminated or further degraded by somebiological process. For clarity, the mechanism of cleavage of the linkeris shown as occurring in stepwise manner. However, both the steps canpossibly occur in a concomitant fashion to release both the drugssimultaneously.

As illustrated in Scheme M3 and M4, Linkers may have additional spacergroups between one side (or both sides) of the linkers and the drugmolecule and some of these spacer groups may be cleaved independently bya chemical or enzymatic process to release the drugs prematurely beforethe cleavage of disulfide linkage. The prodrugs and mutual prodrugscontaining such spacer groups may be useful when faster release ofdrug(s) is desired.

Lists of Candidate Drugs Useful for Prodrug Synthesis:

Drugs listed in the following list can be converted to prodrugs offormula I. This list is in no way limiting the scope of drugs covered inthis invention, but given as representative examples. All the amino-(including amide-NH and sulfonamide-NH, carbamate-NH, sulfamate-NH,hydrazone-NH, semicarbazone-NH, thiosemicarbazone-NH, urea-NH,phosphoramide-NH and the like. See above, for the description of“amino-containing drugs”), carboxyl-, hydroxyl-(including oxime-OH), andcarbonyl (both aldehyde and keto groups)-containing drugs under varioustherapeutic categories as listed in Merck Index (13^(th) editions) andother data bases such as prous science's ensemble, integrity, and thelike and also all the qualified (i.e., amino-, and/or hydroxyl-, and/orcarboxyl-, and/or carbonyl-containing) investigational drugs as listedin databases such Merck Index (13^(th) editions), iddb, ensemble,integrity, and the like, are covered under this invention without anylimitation.

Anti-Inflammatory Drugs:

Amino-containing (including Amide NH and Sulphonamide NH and PhosphomideNH, etc.): Ampiroxicam, Bucolome, Celecoxib, Difenpiramide,Mofebutazone, Nimesulide, Paranyline, Parecoxib, Parsalmide,Piketoprofen, Talniflumate, Tenidap, Terofenamate, and Valdecoxib.

Hydroxyl-containing: 21-Acetoxypregnenolone, Alclometasone,alfa-Bisabolol, Budesonide, Deflazacort, Diflorasone, Desonide,Desoximetasone, Diflorasone, Diflucortolone, Difluprednate, Ditazol,Fluazacort, Fluocinonide, Fluocortin Butyl, Fluprednidene Acetate,Glucametacin, Halcinonide, Halobetasol Propionate, Halometasone,Halopredone Acetate, Ibuproxam, Loteprednol Etabonate, Mazipredone,Mometasone Furoate, Oxyphenbutazone, Perisoxal, Rimexolone.

Hydroxyl-, and Amino-containing (including Amide NH and Sulphonamide NHand Phosphomide NH, etc.): Bufexamac, Etofenamate, Fepradinol,Ibuproxam, Isoxicam, Lornoxicam, Meloxicam, Oxametacine, Piroxicam, andTenoxicam.

Hydroxyl- and sulphahydryl-containing: Tixocortol.

Carboxyl- and Amino-containing (including amide NH and sulphonamide NHand phosphomide NH, etc.): Aceclofenac, Alminoprofen, Amfenac,3-Amino-4-hydroxybutyric Acid, Carprofen, Diclofenac, Enfenamic Acid,Etodolac, Flufenamic Acid, Meclofenamic Acid, Mefenamic Acid, NiflumicAcid, and Tolfenamic Acid.

Carboxyl-containing: Acemetacin, Acetamidocaproic Acid, Bendazac,Benoxaprofen, Bermoprofen, Bucloxic Acid, Butibufen, Cinmetacin,Clidanac, Clopirac, Felbinac, Fenbufen, Fenclozic Acid, Fenoprofen,Fentiazac, Flunoxaprofen, Flurbiprofen, Ibuprofen, Indomethacin,Isofezolac, Isoxepac, Ketoprofen, Lonazolac, Loxoprofen, MetiazinicAcid, Mofezolac, Naproxen, Oxaprozin, Pirazolac, Pirprofen, Pranoprofen,Protizinic Acid, Sulindac, Suprofen, Suxibuzone, Tiaprofenic Acid,Tolmetin, and Tropesin.

Carboxyl- and Hydroxyl-containing: Balsalazide, Enoxolone, Fendosal,Olsalazine, Oxaceprol, and Ximoprofen.

Amino-, Carboxyl- and Hydroxyl-containing: 3-Amino-4-hydroxybutyricAcid, Mesalamine, and Sulfasalazine.

Keto-containing: Nabumetone, and Piketoprofen.

Carboxyl- and keto-containing: Bermoprofen, Bucloxic Acid, Isoxepac,Ketoprofen, Loxoprofen, and Zaltoprofen.

Analgesic and/or Antipyretic Drugs:

Amino-containing: Aminochlorthenoxazin, Aminopropylon, Anileridine,Antrafenine, Benorylate, Benzpiperylon, p-Bromoacetanilide, Butacetin,Carsalam, Difenamizole, Etersalate, Ethenzamide, Ethoxazene, Flipirtine,Isonixin, Nifenazone, Phenacetin, Phenazopyridine, Phenocoll,Phenopyrazone, Piminodine, Piritramide, Propacetamol, Ramifenazone,Piperylone, Salverine, and Tinoridine.

Hydroxyl-containing: Aluminum bis(acetylsalicylate), Benzylmorphine,Buprenorphine, Butorphanol, Chlorobutanol, Ciramadol, Codeine,Desomorphine, Dihydrocodeine, Dihydromorphine, Dihydroxyaluminumacetylsalicylate, Dimepheptanol, Eptazocine, Ethylmorphine, Eugenol,Hydroxypethidine, Levorphanol, Meptazinol, Metazocine, Morphine,Nalbuphine, Pentazocine, Phenazocine, Phenoperidine, Phenylsalicylate,Salicin, Tramadol, and Viminol.

Carboxyl-containing: Acetylsalicylsalicylic acid, Alclofenac, Aspirin,Benoxaprofen, 5-Bromosalicylic acid acetate, Cinchophen, Diacerein,Dipyrocetyl, Fosfosal, Ibufenac, Indoprofen, and Salicysulfuric acid.

Amino- and Hydroxyl-containing: Acetaminophen, Acetaminosalol, Bucetin,Capsaicine, Dezocine, Floctafenine, Glafenine, Isoladol,p-Lactophenetide, Norlevorphanol, Normorphine, Phenylramidol,Salacetamide, and Salicylamide.

Amino- and Carboxyl-containing: Actarit, Bumadizone, Clonixin, andSalicylamide O-acetic acid.

Carboxyl- and Hydroxyl-containing: Diflunisal, Gentisic acid, andSalsalate.

Keto-containing: Amtolmetin, Dipipanone, Hydrocodone, Isomethadone,Methadone, Norpipanone, and Phenadoxone.

Hydroxy- and Keto-containing: Hydromorphone, Ketobemidone, Metopon,Oxycodone, and Oxymorphone.

Carboxyl- and Keto-containing: Clometacin, Ketorolac, and Zomepirac.

Amino- Carboxyl- and Keto-containing: Bromfenac.

Antihypertensive Drugs:

Amino-containing: Alfuzosin, Benzylhydrochlorothiazide, Bethanidine,Bopindolol, Budralazine, Bunazosin, Ciclosidomine, Clonidine, Clopamide,Cyclopenthiazide, Debrisoquin, Edeserpidine, Diazoxide, Dihydralazine,Doxazosin, Endralazine, Guanabenz, Guanacline, Guanazodine,Guanethidine, Guanochlor, Guanadrel, Guanfacine, Guanoxan,Hydracarbazine, Hydralazine, Hydroflumethiazide, Indapamide, Indoramin,Irbesartan, Ketanserin, Lofexidine, Mebutamate, Mecamylamine, Methyl4-pyridyl ketone thiosemicarbazone, Mibefradil, Minoxidil, Monatepil,Moxonidine, Pheniprazine, Pinacidil, Prazosin, Raubasine, Rescinnamine,Reserpiline, Reserpine, Rilmenidine, Syrosingopine, Tasosartan,Terazosin, Tiamenidine, Todralazine, Tolonidine, Tripamide, andUrapidil.

Hydroxy-containing: Ajmaline, Cicletanine, Levcromakalim, Naftopidil,Phenactropinium chloride, and Protoveratrines.

Carboxyl-containing: Eprosartan, Fosinopril, and Telmisartan,

Amino- and Carboxyl-containing: Alacepril, gama-Aminobutyric acid,Benazepril, Candesartan, Carmoxirole, Caronapril, Cilazapril, Detapril,Enalapril, Enalaprilat, Imidapril, Lisinopril, Moexipril, Moveltipril,Perindopril, Quinapril, Ramipril, Saralasin, Spirapril, Temocapril,Trandolapril, and Valsartan.

Amino- and Hydroxyl-containing: Acebutolol, Alprenolol, Amosulalol,Arotinolol, Atenolol, Betaxolol, Bisoprolol, Bosentan, Bucindolol,Bufeniode, Bunitrolol, Bupranolol, Butofilolol, Cadralazine, Celiprolol,Carazolol, Carteolol, Cetamolol, Carvedilol, Epanolol, Indenolol,Nadolol, Dilevalol, Fenoldopam, Guanoxabenz, Labetalol, Losartan,Mepindolol, Metipranolol, Metoprolol, Moprolol, Nebivolol, Olmesartan,Oxprenolol, Penbutolol, Phentolamine, Pildralazine, Pindolol,Propranolol, Rescimetol, Sulfinalol, Talinolol, Tertatolol, Timolol, andTrimazosin.

Amino-, Hydroxyl- and Carboxyl-containing: Methyldopa, and Sampatrilat,Sulfahydryl- and Carboxyl-containing: Captopril, and Omapatrilat,Carbonyl-containing: Aranidipine, and Eplerenone,

Antibiotics:

All the known amino-, hydroxyl-, and carboxyl-containing antibioticssuch as Amoxicillin, Ampicillin, Olivanic acid, Metronidazole, and thelike as listed in Merck Index. 13^(th) edition and other drug databasesintegrity, ensemble, iddb, and the like. These antibiotics can be usedin combination with beta-lactamase inhibitor such as clavulanic acid,penicillinic acid sulfone and the like. The following lists ofantibacterial and antifungal agents are given for clarity.

Antibacterial Agents:

Amino-containing: Acedapsone, Acetosulfone sodium, Ambazone,Bacampicillin, Benzylsulfamide, Brodimoprim, Cefcapene pivoxil,Cefpodoxime proxetil, Chloramine-B, Chloramine-T, Capreomycin,Clofazimine, Cyacetacide, Cycloserine, Dapsone, Ethionamide, Furazoliumchloride, N2-Formylsulfisomidine, Furonazide, Isoniazid, Lenampicillin,Linezolide, Mafenide, 4′-(Methylsulfamoyl)sulfanilanilide,Morphazinamide, Nifuradene, Nitrofurantoin, Penamecillin, Penethamatehydriodide, Pexiganan, Pivampicillin, Pivcefalexin, Picloxydine,Protionamide, Pyrazinamide, Solasulfone, Subathizone,4,4′-Sulfinyldianiline, Sulfoxone sodium, 4′-Sulfanilylsulfanilamide,Sulfoniazide, Sulfabenzamide, Sulfacetamide, Sulfachlorpyridazine,Sulfacytine, Sulfadiazine, Sulfadicramide, Sulfadimethoxine,Sulfadoxine, Sulfaethidole, Sulfaguanidine, Sulfaguanole, Sulfalene,Sulfamerazine, Sulfameter, Sulfamethazine, Sulfamethizole,Sulfamethomidine, Sulfamethoxazole, Sulfamethoxypyridazine,Sulfamethylthiazole, Sulfametrole, Sulfamidochrysoidine, Sulfamoxole,Sulfanilamide, p-Sulfanilylbenzylamine, Sulfanilylurea,N-Sulfanilyl-3,4-xylamide, Sulfaperine, Sulfaphenazole, Sulfaproxyline,Sulfapyrazine, Sulfasomizole, Sulfasymazine, Sulfathiazole,Sulfathiourea, Sulfisomidine, Sulfisoxazole, Sultamicillin,Sulfatolamide, Talampicillin, Taurolidine, Tetroxoprim, Thiazosulfone,Thiacetazone, Tiocarlide, and Trimethoprim.

Hydroxyl-containing: Azithromycin, Chloroxylenol, Chlorquinadol,Clofoctol, Cloxyquin, Diathymosulfone, Glucosulfone sodium,Nifurpirinol, Nifurtoinol, Nitroxoline, Roxarsone, Roxithromycin,Xanthocillin, and Xibornol.

Carboxyl-containing (including sulfate, phosphate andphosphonate-containing): Amdinocillin, Cinoxacin, Difloxacin,Fosfomycin, and Hydnocarpic acid.

Amino- and Carboxyl-containing (including sulfate-, sulfonic acid-,phosphate and phosphonate-containing): Acediasulfone, Amphomycin,Ampicillin, Azidocillin, Azlocillin, Aztreonam, Bacitracin,Balofloxacin, Betamipron, Carbenicillin, Carindacillin, Carumonam,Cefaclor, Cefazedone, Cefazolin, Cefclidin, Cefditoren, Cefepime,Cefetamet, Cefixime, Cefmenoxime, Cefmetazole, Cefodizime, Ceforanide,Cefotaxime, Cefotetan, Cefotiam, Cefoxitin, Cefozopran, Cefpimizole,Cefpirome, Cefroxadine, Cefsulodin, Ceftazidime, Cefteram, Ceftezole,Ceftibuten, Ceftizoxime, Ceftriaxone, Cefuroxime, Cefuzonam,Cephacetrile sodium, Cephalexin, Cephaloglycin, Cephaloridine,Cephalosporin C, Cephalothin, Cephapirin sodium, Cephradine, Cilastatin,Ciproflaxacin, Clinafloxacin, Clometocillin, Cyclacillin, Dicloxacillin,Enoxacin, Epicillin, Fenbenicillin, Floxacillin, Hetacillin, Loracarbef,Metampicillin, Methicillin, Mezlocillin, Nafcillin, Noprysulfamide,Opiniazide, Oxacillin, Penicillin(s), Penimepicycline, Phenethicillin,Phthalylsulfacetamide, Phthalylsulfathiazole, Piperacillin, Propicillin,Quinacillin, Succinylsulfathiazole, Succisulfone, Sulbenicillin,Sulfachrysoidine, Sulfanilic acid, Temocillin, Ticarcillin, andTigemonam.

Amino- and Hydroxyl-containing: Amikacin, p-Aminosalicylic acidhydrazide, Arbekacin, Azidamfenicol, Bambermycins,5-Bromosalicylhydroxamic acid, Butirosin, Clindamycin, Clomocycline,Chloramphenicol, Cloxacillin, Colistin, Demeclocycline,Deoxydihydrostreptomycin, Dibekacin, Dihydrostreptomycin, Dirithromycin,Doxycycline, Enviomycin, Ethambutol, Forimicins, Gentamycin,Glyconiazide, N4-beta-D-Glucosylsulfanilamide, Gramicidin(s),Isepamicin, Kanamycin(s), Lincomycin, Meclocycline, Methacycline,Micronomicin, Neomycin, Netilmicin, Novobiocin, Paromomycin, Phenylaminosalicylate, Pipacycline, Polymyxin, Primycin, Ramoplanin,Ribostamycin, Rifabutin, Rifalazil, Rifamide, Rifamycin SV, Rifampin,Rifapentine, Rifaximin, Ristocetin, Salinazid, Sancycline, Sisomicin,Streptolydigin, Streptomycin, Streptonicozid,2-p-Sulfanilylanilinoethanol, Thiamphenicol, Thiostrepton, Tobramycin,Tuberactinomycin, Viomycin, and Virginiamycin.

Hydroxyl- and Carboxyl-containing (including sulfate, phosphate andphosphonate-containing): Fropenem, Nadifloxacin, Biapenem, Fusidic acid,and Merbromin.

Hydroxyl- and Aldehyde-containing: Josamycin, Leucomycins, Midecamycins,Miokamycin, Rokitamycin, and Spiramycin.

Amino-, Hydroxyl-, and Carboxyl-containing (including sulfate, phosphateand phosphonate-containing): p-Aminosalicylic acid, Apicycline,Amoxicillin, Apalcillin, Aspoxicillin, Benzoylpas, Cefadroxil,Cefamandole, Cefatrizine, Cefbuperazone, Cefdinir, Cefminox, Cefonicid,Cefoperazone, Cefoselis, Cefpiramide, Cefprozil, Ertapenem, Flomoxef,Imipenem, Lymecycline, Meropenem, Moxalactam, Negamycin, Panipenem,Ritipenem, Salazosulfadimidine, Sulfaloxic acid,4-Sulfanilamidosalicylic acid, Teicoplanin, Tyrocidine, and Vancomycin.

Keto-containing: Troleandomycin.

Hydroxy- and Keto-containing: Carbomycin, Clarithromycin, Erythromycin,all erythromycin ester derivatives, Oleandomycin, and Telithromycin.

Hydroxy-, Aldehyde-, and Keto-containing: Rosaramicin.

Amino- and Keto-containing: Porfiromycin.

Carboxyl- and Keto-containing: Fleroxacin, Flumequine, Miloxacin,Nalidixic acid, Ofloxacin, Oxolinic acid, Pefloxacin, Piromidic acid,Prulifloxacin, Rosoxacin, and Rufloxacin.

Amino-, hydroxyl-, and Keto-containing: Chlortetracycline, Dalfopristin,Guamecycline, Mikamycin, Minocycline, Oxytetracycline, Pristinamycin,Quinupristin, Rolitetracycline, Spectinomycin, and Trospectomycin.

Amino-, carboxyl-, and keto-containing: Garenoxacin, Gatifloxacin,Gemifloxacin, Grepafloxacin, Lomefloxacin, Moxifloxacin, Norfloxacin,Pazufloxacin, Pipemidic acid, Sitafloxacin, Sparfloxacin, Tosufloxacin,and Trovafloxacin.

Sulfahydryl-containing: Pyrithione.

Antifungal Agents:

Amino-containing: Chlordantoin, Exalamide, Flucytosine, Loflucarban,Magenta I, and Pyrrolnitrin.

Hydroxy-containing: Chlorphenesin, Ciclopirox, Dermostatin, Filipin,Fluconazole, Fungichromin, Pecilocin, Posaconazole, Ravuconazole,Rubijervine, Siccanin, 2,4,6-Tribromo-m-cresol and Voriconazole.

Carboxyl-containing: Undecylenic acid (10-undecenoic acid), andPropionic acid,

Amino- and Carboxyl-containing: Azaserine.

Amino- and Hydroxyl-containing: Salicylanilide, Acrisorcin(9-Aminoacrindine compound with 4-Hexylresorcinol (1:1)), Anidulafungin,Bromosalicylchloranilide, Buclosamide, Caspofungin, Micafungin, andTubercidin.

Amino-, Carboxyl- and Hydroxyl-containing: Natamycin, Amphotericin B,Lucensomycin, and Nystatin.

Carbonyl-containing: sodium propionate and griseofulvin.

Hydroxy- and carbonyl-containing: Viridin.

Amino-, hydroxyl-, and carbonyl-containing: Perimycin and Mepartricin.

Amino-, carboxyl-, hydroxyl-, and carbonyl-containing: Candicidin.

Antiviral Drugs:

Hydroxy-containing: Edoxudine, Floxuridine, Idoxuridine, Kethoxal,Podophyllotoxin, Sorivudine, Stavudine, Trifluridine, and Zidovudine.

Amino-containing: Amantadine, Amidinomycin, Atevirdine, Capravirine,Delavirdine, Efavirenz, Famciclovir, Imiquimod, Lamivudine, Methisazone,Moroxydine, Nevirapine, Oseltamivir, Rimantadine, Stallimycin,mantadine, and Valacyclovir.

Amino- and Hydroxyl-containing: Abacavir, Acyclovir, Adefovir,Amprenavir, Atazanavir, Cidofovir, Didanosine, Dideoxyadenosine,Emtricitabine, Entecavir, Indinavir, Lamivudine, Lopinavir,5-(methylamino)-2-deoxyuridine (MADU), Nelfinavir, Penciclovir,Resiquimod, Ribavirin, Ritonavir, Saquinavir, Tenofovir, Tipranavir,Valganciclovir, Vidarabine, and Zalcitabine.

Carboxyl- and Hydroxyl-containing: Foscarnet sodium, and Ganciclovir.

Amino-, Carboxyl- and Hydroxyl-containing: Zanamivir.

Antimalarial:

Amino-containing: Chlorguanide, Chloroquine, Chlorproguanil,Cycloguanil, Pamaquine, Plasmocid, Primaquine, Quinocide, andTafenoquine.

Hydroxyl-containing: Artemisinin alcohol, Bebeerines, Cinchonidine,Cinchonine, Dihydroartemisinin, Halofantrine, Lumefantrine, Quinine andYingzhaosu A.

Carboxyl-containing: Arteflene and Artesunate.

Amino-, and Hydroxyl-containing: Amodiaquin, Hydroxychloroquine,Mefloquine, and Pyronaridine.

Hydroxyl, and carbonyl-containing: Fosmidomycin.

Carbonyl-containing: Arteflene.

Antineoplastic Drugs:

Hydroxy-containing: Aclacinomycins, Arzoxifene, Batimastat, Broxuridine,Calusterone, Capecitabine, CC-1065, Chromomycins, Diethylstilbestrol,Docetaxel, Doxifluridine; Droloxifene, Dromostanolone, Enocitabine,Epitiostanol, Estramustine, Etanidazole, Etoposide, Fenretinide,Flavopiridol, Formestane, Fosfestrol, Fulvestrant, Gemcitabine,Irinotecan, Melengestrol, Menogaril, Miltefosine, Mitobronitol,Mitolactol, Mopidamol, Nitracrine, Nogalamycin, NordihydroguaiareticAcid, Olivomycins, Paclitaxel and other known paclitaxel analogs,Plicamycin, Podophyllotoxin, Retinoic acid (including all trans-retiniocacid), Roquinimex, Rubitecan, Seocalcitol, Temoporfin, Teniposide,Tenuazonic Acid, Topotecan, Valrubicin, Vinblastine, Vincristine, andZosuquidar.

Amino-containing (including Amide-NH and Sulphonamide-NH, Carbamate-NH,Sulfamate-NH, and Phosphomide-NH): 9-Aminocamptothecin, AminolevulinicAcid, Amsacrine, Bisantrene, Cactinomycin, Carboquone, Carmofur,Carmustine, Cyclophosphamide, Dacarbazine, Dactinomycin, Demecolcine,Diaziquone, 6-Diazo-5-oxo-L-norleucine (DON), Edatrexate, Efaproxiral,Eflornithine, Eniluracil, Erlotinib, Fluorouracil, Gefitinib,Gemcitabine, Goserelin, Histamine, Ifosfamide, Imatinib, Improsulfan,Lanreotide, Leuprolide, Liarozole, Lobaplatin, Cisplatin, Carboplatin,Lomustine, Lonafarnib, Mannomustine, Melphalan, Methotrexate, MethylAminolevulinate, Miboplatin, Mitoguazone, Mitoxantrone, Nilutamide,Nimustine, Nolatrexed, Oxaliplatin, Pemetrexed, Phenamet, Piritrexim,Procarbazine, Raltitrexed, Tariquidar, Temozolomide, Thiamiprine,Thioguanine, Tipifarnib, Tirapazamine, 3-Aminopyridine-2-carboxaldehydethiosemicarbazone (3-AP)/3-Aminopyridine-4-methyl-2-carboxaldehydethiosemicarbazone (3-AMP/Triapine/OCX-191/OCX-0191), Trimetrexate,Uracil Mustard, Uredepa ([Bis(1-aziridinyl)phosphinyl]carbamic acidethyl ester, ethyl carbamate and Meturedepa.

Both Hydroxy- & Amino-containing (including Amide-NH andSulphonamide-NH, Carbamate-NH, Sulfamate-NH, and Phosphomide-NH):Ancitabine, Anthramycin, Azacitidine, Bleomycins, Bropirimine,Buserelin, Carubicin, Chlorozotocin, Cladribine, Cytarabine,Daunorubicin, Decitabine, Defosfamide, Docetaxel, Doxorubicin,Ecteinascidins, Epirubicin, Gemcitabine, Hydroxyurea, Idarubicin,Marimastat, 6-Mercaptopurine, Pentostatin, Peplomycin, Perfosfamide,Pirarubicin, Prinomastat, Puromycin, Ranimustine, Streptonigrin,Streptozocin, Tiazofurin, Troxacitabine, Vindesine and Zorubicin.

Carboxyl-containing: Butyric acid.

Antioxidants/Free Radical Scavengers:

Amino-containing (including some investigational drugs): BTX-51072(4,4-dimethyl-3,4-dihydro-2H-1,2-benzoselenazine), Carnosine, Melatonin,(+)-R-Pramipexole, and Stobadine.

Hydroxyl-containing (including some investigational drugs): Ascorbicacid, Curcumin, Dexanabinol, Edaravon, (−) Epigallocatechin Gal late,Emoxipin, Hydroxytyrosol, Idebenone, Luteolin, Nicanartine, NZ-419,Oxyresveratrol, Probucol (including probucol prodrugs such as AGI-1067and AGI-1096), Quercetin, Reductic acid, Silybin, Tempol(4-Hydroxy-TEMPO), and alfa-Tocopherol (Vitamin E).

Carboxyl-containing (including some investigational drugs): N-AcetylL-cysteine, Alfa-Lipoic acid, Raxofelast, and Tetomilast.

Amino-/Hydroxyl-, and Carboxyl-containing (including someinvestigational drugs): N-Acetyl carnosine, L-Carnitine, and SCMC-Lys(S-carboxymethyl-L-cysteine Lysine salt H₂O).

Amino- and Hydroxyl-containing (including some investigational drugs):BN-82451, and Zeatin.

Benzodiazepine Tranquilizers and Hypnotics:

Diazepam, Triazolam, Alprazolam, and the like.

Antiulcer Agents:

Amino-containing (including Amide NH and Sulphonamide NH and PhosphomideNH, etc.): Aldioxa, Benexate HCl, Cimetidine, Ebrotidine, Ecabapide,Esaprazole, Esomeprazole, Famotidine, Irsogladine, Lafutidine,Lansoprazole, Omeprazole, Pantoprazole, Pirenzepine, Polaprezinc,Rabeprazole, Ranitidine, Roxatidine, and Troxipide.

Hydroxyl (and Keto and Keto and/or Carboxyl)-containing: Enprostil,Misoprostol, Ornoprostil, Plaunotol, Rioprostil, Trimoprostil, andOryzanol A.

Carboxyl-containing: Acetoxolone, Carbenoxolone, Rebamipide, andSofalcone.

Amino (or Hydroxyl)- and Carboxyl-containing: Cetraxate, Ecabet,S-Methylmethionine, Rosaprostol, and Rotraxate.

Carbonyl-containing: Spizofurone, and Teprenone.

Anticonvulsants:

Amino-containing (including Amide NH and Sulphonamide NH and PhosphomideNH, etc.): Acetylpheneturide, Albutoin, N-benzyl-3-chloropropionamide,Carbamazepine, Cinromide, Clonazepam, Decimemide, Dimethadione,Doxenitoin, Ethosuximide, Ethotoin, Felbamate, Fosphenyloin,Lamotrigine, Levetiracetam, Mephenyloin, Mephobarbital, Metharbital,Methetoin, Nitrazepam, Oxcarbazepine, Oxicarbamazepine, Phenacemide,Phenetharbital, Pheneturide, Phenobarbital, Phenylmethylbarbituric Acid,Phenyloin, Phethenylate Sodium, Primidone, Progabide, Remacemide,Rufinamide, Suclofenide, Sulthiame, Talampanel, Tetrantoin, Topiramate,Valpromide, Zonisamide, 5-Methyl-5-(3-phenanthryl)hydantoin, and3-Methyl-5-phenylhydantoin.

Hydroxyl-containing: Ganaxolone.

Hydroxyl-, and Amino-containing (including Amide NH and Sulphonamide NHand Phosphomide NH): 4-Amino-3-hydroxybutyric Acid, Atrolactamide, andBuramate.

Carboxyl- and Amino-Containing (including Amide NH and Sulphonamide NHand Phosphomide NH): Gabapentin, Pregabalin, and Vigabatrin.

Carboxyl-containing: Tiagabine, and Valproic Acid.

Antiparkinson'S: Levodopa & Carbidopa.

Antidepressant:

Amino-containing (including Amide NH and Sulphonamide NH and PhosphomideNH, etc.): Amoxapine, Caroxazone, Demexiptiline, Desipramine,Duloxetine, Fluoxetine, Fluvoxamine, Indalpine, IndeloxazineHydrochloride, Iproclozide, Iproniazid, Isocarboxazid,Levophacetoperane, Maprotiline, Metapramine, Milnacipran, Minaprine,Moclobemide, Nialamide, Nomifensine, Nortriptyline, Octamoxin,Oxypertine, Paroxetine, Protriptyline, Reboxetine, Rolipram, Sertraline,Tofenacin, Tranylcypromine, Viloxazine, Benmoxine, and Rolicyprine.

Hydroxyl-containing: Befloxatone, Bupropion, Fenpentadiol, Hypericin,Opipramol, Pyrisuccideanol, Toloxatone, and Venlafaxine.

Hydroxyl-, and Amino-containing (including Amide NH and Sulphonamide NHand Phosphomide NH): S-Adenosylmethionine, 5-Hydroxytryptophan, andRoxindole.

Carboxyl- and Amino-Containing (including Amide NH and Sulphonamide NHand Phosphomide NH): Amineptine, and Tianeptine.

Antihistaminic

Amino-containing (including Amide NH and Sulphonamide NH and PhosphomideNH, etc.): Antazoline, Astemizole, Clobenzepam, Desloratadine,Epinastine, Metron S, Mizolastine, and Tritoqualine.

Hydroxyl-containing: Terfenadine, and N-HydroxyethylpromethazineChloride.

Hydroxyl-, and Amino-containing (including Amide NH and Sulphonamide NHand Phosphomide NH, etc.): Cetoxime.

Carboxyl-containing: Acrivastine, Bepotastine, Cetirizine, andLevocabastine,

Carboxyl- and Hydroxyl-containing: Fexofenadine.

Anticancer, Antioxidative, Antiinflammatory, and Cardioprotective Agent:Trans-Resveratrol [(E)-3,4′,5-Trihydroxystilbene).

Antidiabetic: Metformin, and Nateglinide/Glipizide/Glibenclamide(Glyburide).

It should be understood that while the lists of names of variouscategories of drugs have been included above, such lists are presentedin a way of illustration of the structural features of the qualifyingdrugs in this invention and therefore, the number and types of listeddrugs are not necessarily limited thereto. In principal, any amino-,and/or carboxyl, and/or carbonyl-, and/or hydroxyl-containing drug (fromboth known and investigational drugs), irrespective of its therapeuticcategory and their mechanism of action, as listed in drug databases suchas Merck Index, prous science's ensemble, integrity, iddb, and the like,are generally covered within the true spirit and scope of the presentinvention. For clarity, in addition to the above lists of drugs, anyamino-, and/or carboxyl-, and/or carbonyl-, and/or hydroxyl-containingdrug(s) (both known and investigational drugs) from the followingtherapeutic areas are covered without any limitation:

CENTRAL NERVOUS SYSTEM: Sedatives, Hypnotics, Antidepressants,Antipsychotics and Antimanics, Analgesics & Antipyretics, Antimigraineagents, Anticonvulsants, Drugs used in parkinsonism and movementdisorders, Drug for dementia, Antiemtics, drugs for Vertigo, CNSStimulants & activators.

EYE: Antiinfective eye preparations, Antiinflammatory and antiallergicpreparations, antiglucoma drugs and other preparations to cure eyediseases.

EAR, NOSE and OROPHARYNX: Drugs used aural, nasal and oropharyngealpreparation.

CARDIOVASCULAR SYSTEM: Antiarrhythemic drugs, Antihypertensives(including alfa/beta-blockers, channel blockers, ACE inhibitors,Angiotensin II receptor antagonists, diuretics, etc.), Antianginals(including nitrates, calcium channel blockers, etc.), Drugs for cardiacfailure and shock, Vasodilators, Coagulants, Anticoagulants,Thrombolytics and antiplatelet drugs.

RESPIRATORY SYSTEM: Respiratory stimulants, Antitussives, Expectorants,Mucolytics and Decongestants, Antihistamine agents, and antiasthmatics.

GASTRO INTESTINAL TRACT: Antiulcer and Antisecretory drugs (including H₂receptor antagonists, Proton Pump Inhibitors, Prostaglandin analogues,etc.), Antacids, Antispasmodics and drugs modifying intestinal motility,Antidiarrhoeals (including antimotility and antimicrobial drugs) anddrugs acting on gall bladder.

GENITO URINARY SYSTEM: Urinary antiinfectives, Diuretics, Urinaryanalgesics & antispasmodics, Antiinfective drugs acting on urethra andvagina, drugs acting on uterus, Drugs for prostatic hypertrophy(including alfa blockers and antiandrogens), Drugs for erectiledysfunction, and Spermicidal & nonhormonal contraceptives.

SKIN: Emollients and keratolytics, topical antiinfectives, topicalantifungals, topical parasiticidals, topical steroids, topical drugs foracne vulgaris, drugs for psoriasis, pigmentation disorders, and Antiseborrhoeics.

MUSCULO-SKELETAL DISORDERS: Non Steroidal Anti Inflammatory Drugs(NSAIDs) including COX-2 inhibitors, Antiarthritic agents,Immunosuppressants, Topical analgesics, Muscle relaxants andNeuromuscular Drugs.

INFECTIONS AND INFESTATIONS: Penicillin antibiotics, Cephalosporinantibiotics, Quinolone & Fluoroquinolone antibiotics, Macrolideantibiotics, Chloramphenicol, Tetracycline antibiotics, Sulfonamides,Antianaerobics such as Metronidazole, Antitubercular drugs, Antileprosydrugs, Antifungals, Antiprotozoals, Anthelminthics & AntiinfectiveDrugs, Antimalarials and Antivirals.

ENDOCRINE SYSTEM: Anabolic and androgenic steroids, Corticosteroids,Oestrogens, Progestogens and Hormonal contraceptives, Fertility Agents,Trophic hormones and related drugs, Thyroid and antithyroid drugs,Antidiabetics and hyperglycaemics.

NUTRITION: Vitamins, Amino acids, Anti-obesity drugs

METABOLISM: Hypolipidaemic drugs (including fibric acid derivatives,statins [(i.e., HMG CoA reductase inhibitors), nicotinic acid group,etc.], Drugs used for Gout and Drugs affecting bone metabolism(including bisphosphonates).

NEOPLASTIC DISORDERS: Anticancer drugs such as alkylating agents,cytotoxic antibiotics, antimetabolites such as cytarbine, Fludarbine,5-Fluorouracil, Mercaptopurine, Thioguanine, etc., Vinca alkaloids andEtoposide, Taxanes, Topoisomerase 1 inhibitors, Cytotoxicimmunosuppressants, Immunostmulants, Cytoprotectives such as Amifostine,Oestrogens, Progestogens, hormon antagonists and other antineoplasticdrugs.

ALLERGY AND IMMUNOLOGY: Antiallurgics such as non-sedative antihistamins(e.g., Cetirizine, Desloratadine, Terfenadine, Fexofenadine, etc.),sedative histamines and histamine receptor blockers.

ANAESTHETICS & SURGICALS: Local anaesthetics, intravenous anaesthetics,inhalation anaesthetics and muscle relaxants.

Drug Combinations:

It is appreciated that prodrugs of any two or more drugs from the abovelists of potential drugs can be used in combination depending on themedical application/need. While a combination formulation mayoccasionally consist of more than two drugs (depending on the medicalneed), the following pairs of drugs are covered in this invention asillustrative pairs of candidate drugs for combination therapy.

ANTICANCER: Paclitaxel and Doxorubicin, Paclitaxel and Mitomycin C;Paclitaxel and 9-aminocamptothecin, 3-Aminopyridine-2-carboxaldehydethiosemicarbazone (3-AP)/3-Aminopyridine-4-methyl-2-carboxaldehydethiosemicarbazone (3-AMP) and another known anticancer drug such asPaclitaxel, Doxorubicin, Mitomycin C and the like; CC-1065 and anotherknown anticancer drug such as Paclitaxel, Doxorubicin, Mitomycin C andthe like; Trans-Resveratrol [(E)-3,4′,5-trihydroxystilbene) and anotherknown anticancer drug such as Paclitaxel, Doxorubicin, Mitomycin C andthe like; Retinoic acid (including all trans-retinoic acid) and Butyricacid. Paclitaxel and Captopril, Doxorubicin and Biotin. 5-Fluorouraciland Cytarabine. Edatrexate and Paclitaxel; Cephalosporanic acid andPaclitaxel; Cephalosporin and Paclitaxel; and Paclitaxel andGemcitabine.

ANTIPARKINSON'S: Levodopa and Carbidopa.

ANTIBIOTICS: Amoxicillin and Clavulanic acid; Ampicillin and Clavulanicacid, Amoxicillin and Pencillinic acid sulfone; Ampicillin andPencillinic acid sulfone; Olivanic acid (or any carbapenem antbiotic)and a renal dipeptidase (dehydropeptidase I) inhibitor such as3-substituted Z-2-acylaminopropionic acid and the like.

ANTILIPIDEMIC AND HYPERTENSION: Lifibrol andLovastatin/Pravastatin/Fluvastatin/Atorvastatin/Simvastatin; Ezetimibeand Lovastatin/Pravastatin/Fluvastatin/Atorvastatin/Simvastatin;

Amlodipine andLovastatin/Pravastatin/Fluvastatin/Atorvastatin/Simvastatin.

ANTIDIABETIC: Metformin and Nateglinide/Glipizide/Glibenclamide(Glyburide)

ANTIDIABETIC AND HYPERTENSION: Metformin andLovastatin/Pravastatin/Fluvastatin/Atorvastatin/Simvastatin.

ANTIASTHMATIC, ALLERGIC RHINITIS AND CHRONIC OBSTRUCTIVE PULMONARYDISEASE (COPD): Pseudoephedrine andFexofenadine/Cetirizine/Desloratadine/Epinastine; Salbutamol andIpratropium bromide; Mometasone and Formoterol/Salmeterol; Fluticasoneand Formoterol/Salmeterol; Budesonide and Formoterol/Salmeterol.

ANTIARTHRITIS, INFLAMMATION AND ULCERS: Diclofenac (any known NSAID) andMisoprostol; Diclofenac (any known NSAID) and a proton pump inhibitorsuch as Omeprazole, Lansoprazol, Rabeprazole, Leminoprazole,Pantoprazole, and the like; A known antibacterial agent and a protonpump inhibitor such as Omeprazole, Lansoprazol, Rabeprazole,Leminoprazole, Pantoprazole, and the like; Naproxen (or any known NSAID)and Prophenazone; Acetaminophen andchlorzoxazone/metaxalone/mephenoxalone.

ANTIVIRAL (HIV/AIDS, HEPATITIS B AND OTHER VIRAL INFECTIONS): Zidovudineand Lamivudine; Triple prodrug of Zidovudine; Lamivudine and Abacavir(Ziagen); Lopinavir and Ritonavir; Lamivudine and Adefovir or itsprodrug adefovir dipivoxil; Amprenavir and Zidovudine; Nelfinavir and anucleoside reverse transcriptase inhibitor such as Zidovudine,Lamivudine, and the like; Stavudine and an antiretroviral agent such asZidovudine, Lamivudine, and the like; Dideoxyinosine and anantiretroviral agent such as Zidovudine, Lamivudine, and the like;Emtricitabine and Penciclovir/Famciclovir; Acyclovir (or any other knownantiviral compound) and a bile acid such as cholate, deoxycholate,chenodeoxycholate, and ursodeoxycholate (for targeting bile acidtransporters for enhanced oral bioavailability of the drug; Triple andprodrug of Zidovudine, Lamivudine and Efavirenz.

In addition to the above list of drugs, the present invention alsocovers newer drugs with the above mentioned active functional groups aslisted in the Merck index (13^(th) edition) and other drug databasessuch as Prous Science's ensemble, integrity and the investigationaldrugs as listed in databases such as iddb, ensemble, integrity, and thelike without any limitation.

It should be understood that either or both of any selected pair ofdrugs (in any proportion) can be in the form of nitrate ester(NO-releasing) prodrug(s) of formula (I) or pharmaceutically acceptablesalts thereof and the other drug can be in its native form. For clarity,let us assume that Ibuprofen and Paracetamol are present as activeprinciples in a pharmaceutical composition. Then, either or both ofthese drugs can be in their prodrug form (i.e., NO-Paracetamol andIbuprofen/Paracetamol and NO-Ibuprofen/NO-Paracetamol and NO-Ibuprofen,etc.) and they can be present in any proportion.

It should also be understood that a pharmaceutical compositionconsisting of two or more of the above listed/qualified drugs, one ofthe drugs can be in the form of NO-releasing (nitrooxy derivative)prodrug and the other drug(s) in the combination can be in the formanother type of prodrug(s).

It should also be understood that a pharmaceutical compositioncontaining a combination of one of the above listed/qualified drug(s)and its own prodrug is also covered (i.e., a pharmaceutical compositionconsisting of NO-Paracetamol and Paracetamol in any proportion). In suchpharmaceutical combinations, the free drug will be useful for fasteronset of action and the prodrug will be useful for extension of theduration of action as it releases the drug in a controlled fashion overa longer period of time. Such combination drug therapy may also minimizethe toxicity and other side effects due to excessive plasmaconcentration of free drug. It should also be understood that apharmaceutical combination may contain a prodrug of one of the abovelisted/qualified drugs and an another type of prodrug of the same drug(i.e., NO prodrug of paracetamol and mutual prodrug of paracetamol withanother drug) and these can be present in any therapeutic proportiondepending on the medical need.

EXPERIMENTAL Abbreviations Used

BOP: Benzotriazol-1-yl-oxy-tris(dimethylamino)phosphoniumhexafluorophosphate

DMF: N,N-Dimethylformamide

DSC: N,N′-Disuccinimidyl carbonate

CDI: N,N′-Carbonyldiimidazole

DTE: Dithioerythritol

DTT: Dithiothreitol

DCC: N,N′-Dicyclohexylcarbodiimide

EDAC. HCl: 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride

HBTU: O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate

TBTU: O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate

EtOH: Ethanol

Et₂O: Diethyl ether

THF: Tetrahydrofuran

DMSO: Dimethyl sulfoxide

TEA: Triethylamine

DIPEA: N,N-Diisopropylethylamine

DCM: Dichloromethane

EtOAc: Ethyl acetate

DME: Dimethoxyethane

MeOH: Methanol

PE: Petroleum ether

RT: Room temperature

TFA: Trifluoroacetic acid

HOBT: N-Hydroxybenzotriazole

Synthetic Methods:

The prodrugs described herein can be prepared by any number of methodsknown/obvious to those skilled in the art. The synthetic approaches andthe linkages are chosen depending upon the functional groups such ascarboxyl, hydroxyl, amino or carbonyl groups present in the drugmolecules to be used. The following illustrative methods, as shown inSchemes 1 through 9, can be utilized to make carbonate, urethane, amide,ester, N-acyl carbamate, N-acyl amide, N-acyl sulfamate, and N-acylsulfonamide, N-acyl phosphoramide, N-oxycarbonylsulfonamide,N-oxycarbonylcarbamate linkages, etc., between drug(s) and linker(s).

Method(s) of Making Carbonate Linkage(s):

As depicted in the scheme 1, the carbonate linkage between the drug andthe linker can be made by reacting the hydroxyl-containing drug(alternatively, hydroxyl group of the linker) with phosgene or itsequivalents such as diphosgene, triphosgene, N,N′-carbonyldiimidazole(CDI), N,N′-disuccinimidyl carbonate (DSC), 4-nitrophenyl chloroformateand the like, to give a reactive alkoxycarbonyl derivative, where LG issuitable leaving group such as a halide, imidazole, O-succinimide,4-nitrophenoxide and the like, which can be reacted with hydroxyl groupof the linker (alternatively, hydroxyl group of drug if the linker isconverted to active alkoxycarbonyl derivative) in the presence of asuitable base and solvent.

Bases such as triethylamine, diisopropylethylamine,4-(dimethylamino)pyridine (DMAP), and the like, can be used. Suitablesolvents include CH₂Cl₂, CHCl₃, DMF, THF, ACN, ethyl acetate, ethylether and the like.

Method(s) of Making Urethane Linkage(s):

As shown in scheme 2, the urethane linkage between the drug and thelinker can be made by reacting the hydroxyl-containing linker withphosgene or its equivalents (defined above) to give a reactivealkoxycarbonyl derivative, which can be reacted with amino-containingdrug in the presence of a suitable base and solvent. Alternatively, aurethane linkage can be made by adding an alcohol to an isocyanate.

-   -   Suitable bases and solvents are same as defined above.        Method(s) of Making Amide or Ester Linkage(s):

As shown in the Scheme 3, an amide or ester linkage between the drug andthe linker can be made by reacting a carboxyl-containing drug with anamino- or hydroxyl-containing linker in the presence of a suitablecoupling agent, base and solvent. Alternatively, the carboxyl-containingcompound can be first converted to reactive carbonyl derivative such asan acid halide, a succinimide ester, a pentafluorophenyl ester, animidazolide and the like, which can be treated with amino-containing orhydroxyl-containing linker in the presence of a suitable base andsolvent to afford the corresponding amide or ester linkage(s),respectively (see, Bodanszky, M. and Bodanszky, A., The Practice ofPeptide Synthesis, Springer-Verlag, New York, 1984)

Suitable coupling agents include DCC, EDCl.HCl, BOP, HBTU, TBTU,DCC/HOBT, EDC/HOBT, and the like. Suitable bases and solvents are sameas defined above.

Method(s) of Making N-Acyl Carbamate and N-Acyl Urea Linkage:

The linkage such as N-acyl carbamate linkage between the linker and drugcan be made as shown in Scheme 4. Thus, treatment of an alcohol withphosgene or its equivalent can yield the correspondingcarbonochloridate, which upon treatment with ammonia gas can give thecorresponding carbamate intermediate. The carbamate nitrogen can beacylated by a suitable carboxylic acid derivatives such as anhydride oracid halide, a succinimide ester, a pentafluorophenyl ester, animidazolide, and the like, in the presence of a suitable base to yieldthe corresponding N-acyl carbamate. Alternatively, N-acyl carbamate canbe made by the reaction of an alcohol with N-acyl isocyanate, which canbe prepared either by the reaction of the corresponding amide withoxalyl chloride (See, Speziale, A. J. et al., J. Org. Chem. 1962, 27,3742; Speziale, A. J. et al., J. Org. Chem. 1963, 28, 1805-1811) or bythe reaction of the corresponding acid chloride with silver cyanate.(See, Hill, A. J. et. al., J. Am. Chem. Soc., 1940, 62, 1595; Kim, D. K.J. Heterocyclic Chem. 1995, 32, 1625).

Suitable bases and solvents are same as defined above.

Method(s) of Making N-Acyl Amide Linkage:

The N-acyl amide linkage between the linker and drug can be made asshown in Scheme 5. Thus, the amide nitrogen can be acylated by asuitable carboxylic acid derivatives such as anhydride or acid halide, asuccinimide ester, a pentafluorophenyl ester, an imidazolide, and thelike, in the presence of a suitable base to yield the correspondingN-acyl amide.

Suitable bases and solvents are same as defined above.

Method(s) of Making N-Acyl Sulfamate Linkage:

The linkage such as N-acyl sulfamate between the linker and drug can bemade as shown in Scheme 6. Thus, treatment of an alcohol with sulfurylchloride in the presence of suitable base gives the intermediatesulfochloridate, which can be converted to the corresponding sulfamate.Acylation of sulfamate nitrogen with a suitable carboxylic acidderivatives such as anhydride or acid halide, a succinimide ester, apentafluorophenyl ester, an imidazolide, and the like, can yield thecorresponding N-acyl sulfamate.

Suitable bases and solvents are same as defined above.

Method(s) of Making N-Acyl/Oxycarbonyl Sulfonamide Linkages:

The N-acyl/oxycarbonyl sulfonamide linkage between the linker and drugcan be made as shown in Scheme 7. Thus, a sulfonamide nitrogen can beacylated by a suitable carboxylic acid derivatives such as anhydride oracid halide, a succinimide ester, a pentafluorophenyl ester, animidazolide, and the like, to yield the corresponding N-acylsulfonamide,which can be metallated using an inorganic base. Similarly, thesulfonamide nitrogen can be acylated by a suitable formyl chloridederivative such as alkyloxycarbonyl chloride, imidazolide and the like,to yield the corresponding N-alkyloxycarbonyl sulfonamide as shown inthe scheme. Alternatively, the same linkage can be made by the reactionof an alcohol with sulfonyl isocyanate which can be prepared by knownmethods such by treatment of sulfonamide with oxalyl chloride (see, HansKrzikalla et al., U.S. Pat. No. 2,666,787 or Smith, J. et al., J. Org.Chem. 1965, 30, 1260-1262) or by treatment of sulfonyl chloride withsilver cyanate (See, Smith, J. et al., J. Org. Chem. 1965, 30,1260-1262).

Suitable bases and solvents are same as defined above.

Method(s) of Making N-Oxycarbonylcarbamate and N-OxycarbonylureaLinkages:

The N-oxycarbonylcarbamate (or N-oxycarbonylurea) linkage between thelinker and drug can be made as shown in Scheme 8. Thus, carbamatenitrogen can be acylated by suitable formyl chloride derivatives such asalkyloxycarbonyl chloride, imidazolide and the like, to yield thecorresponding N-alkyloxycarbonylcarbamate as shown in the scheme.Alternatively, the N-oxycarbonylcarbamate (or N-oxycarbonylurea) linkagebetween the linker and drug can be made by the reaction of an alcohol(or an amine) with carbamoyl isocyanate (IP15A), which can be preparedby known methods such by treatment of carbamate with oxalyl chloride(See, Grehn L, et al., Synthesis, 1988, 922-994) or by treatment of aformyl chloride with silver cyanate (See, Kim, D. K. et al., J.Heterocyclic Chem. 1995, 32, 1625). Alternatively,N-oxycarbonylcarbamate (or N-oxycarbonylurea) can be prepared in twosteps. Step 1: reaction of an alcohol or phenol with chlorocarbonylisocyanate to give N-oxycarbonyl carbamoyl chloride intermediate(IP15B). Step 2: reaction of the intermediate IP15B with the same oranother alcohol or phenol or an amine. (For a review on chemistry ofchlorocarbonyl isocyanate, see, Gorbatenko, V. I. Tetrahedron, 1993, 49,3227).

Suitable bases and solvents are same as defined above.

Method(s) of Making Nitrate (Nitrooxy) or Nitrite (Nitrosyloxy) Esters:

The nitrate or nitrite esters can be made as shown in Scheme 9. Thus, anitrate or nitrite ester can be made by treating an alcohol withHNO₃/H₂SO₄ (or HNO₃/Ac₂O) or nitrosyl chloride, respectively.Alternatively, a nitrate ester can be made by treating a halide (bromideor iodide is preferred) with silver nitrate in a polar aprotic solventsuch as acetonitrile.

Compounds (Prodrugs) of the formula (I) containing bio-cleavable linkersand linkages can be synthesized by various methods obvious to thoseskilled in the art. As a matter of illustration, any of the approachesshown in the following schemes can be used to make such prodrugs of theformula (I) described herein.

Monoprotection of diol or aminoalcohol or diamino compounds [i.e.,linker(s)] with suitable protecting groups and their selective removalat appropriate stage of the synthesis are carried out as described inTheodora W. Greene and Peter G. M. Wuts, “Protective Groups in OrganicSynthesis”, 3^(rd) edition, John Wiley and Sons, Inc. New York (1999),the disclosures of which are incorporated herein by reference. Suitableprotecting groups (PGs) include, but not limited to, acetyl, Boc, Fmoc,benzoyl, pivaloyl, trityl, tetrahydropyranyl (THP), and silyl (TBDMS,TMS, etc.). Obviously, selection of a suitable protecting group is verycrucial for the success of a chosen method for the synthesis of prodrugsdescribed in this invention.

Synthesis of appropriately derivatized/modified bio-labile linker isshown in Scheme 10.

Some of the methods for the synthesis of prodrugs (includingNO-releasing prodrugs) of carboxyl-, amino-, and hydroxyl-containingdrugs are shown in Schemes 11 through 14.

Some of the methods for the synthesis of prodrugs (includingNO-releasing prodrugs and water-soluble prodrugs) are shown in Schemes15 and 16.

Double/Mutual prodrugs described in this invention can be synthesized byany of the approaches depicted in Schemes 17 through 19.

As a matter of illustration, mutual prodrug of desloratadine andpseudoephidrine was synthesized as depicted in Scheme 21.

-   -   Y═O, NR¹ (R¹=H, Alkyl, Aralkyl, Cycloalkyl), (CH₂)_(n)C(═O)        (n=1-6), (CH₂)_(n)CO₂ ⁻    -   Z═C═O, SO₂, P(═O)YR³ (R³=H or a metal ion)    -   R²═H, a bond, CH₂CH₂N(CH₃)₂. HCl, an Amino acid, or any molecule        containing solubilizing groups such as carboxylic acid,        sulphonic acid, hydroxyl, amino groups, polyethyleneglycol        (PEG), a metal ion such a Na⁺, Ca²⁺, etc.

Example 1 Synthesis of 2-[(2-hydroxyethyl)dithio]ethyl acetate (LI-1a)

Acetic anhydride (5.67 ml, 56.87 mmol) and pyridine (40.4 ml, 499 mmol)were added to a solution of 2-(hydroxyethyl)disulfide (SL-1, 15.39 g,99.78 mmol) in DCM (350 mL) at RT and the mixture was stirred at RT for16 h. The mixture was concentrated and the residue, after usual aqueouswork-up and chromatographic purification, afforded 8.16 g (42%) of LI-1aas a pale yellow oil. ¹H-NMR (300 MHz, CDCl₃): δ 2.00 (bs, 1H), 2.08 (s,3H), 2.80-2.95 (m, 4H), 3.89 (t, 2H, J=6 Hz), 4.35 (t, 2H, J=6 Hz), MS:(m/z) 219 [M]⁺.

Example 2 Synthesis of2-{[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]dithio}ethanol (LI-1b)

This compound was synthesized by a method described by K. F. Bernady etal., J. Org. Chem., 1979, 44, 1438. Dihydropyran (8.41 g, 100 mmol) wasadded to a solution of SL-1 (15.4 g, 100 mmol) in DCM (200 mL) at 0-5°C., followed by PTSA (˜5%) and stirred at RT for 5 h. The mixture, afterusual aqueous work-up and chromatographic purification, afforded 14.5 g(50%) of LI-1b. ¹H-NMR (300 MHz, CDCl₃): δ 1.5-1.9 (m, 6H), 2.88 (t, 2H,J=6 Hz), 2.94 (t, 2H, J=6 Hz), 3.45-3.57 (m, 1H), 3.67-3.78 (m, 1H),3.85-4.05 (m, 2H), 3.90 (t, 2H, J=6 Hz), 4.65 (s, 1H).

Example 3 Synthesis of 2-{[2-(Trityloxy)ethyl]dithio}ethanol (LI-1c)

This compound was synthesized by a method described by O. Hernandez etal., Tetrahedron Letters, 1981, 22, 1491-1494. Thus, 8.58 g (21.4 mmol)of 4-dimethylamino-N-triphenylmethylpyridinium chloride (A. V. Bhatia etal., Organic Synthesis, 1997, 75, 184-185) was added to a solution ofSL-1 (3.0 g, 19.45 mmol) in DCM (90 mL) and stirred at RT for 24 h. Themixture, after usual aqueous work-up and chromatographic purification,afforded 2.86 g (37%) of LI-1c. ¹H-NMR (300 MHz, CDCl₃): δ 2.70 (t, 2H,J=6.0 Hz), 2.88 (t, 2H, J=6.0 Hz), 3.39 (t, 2H, J=6.0 Hz), 3.80 (q, 2H,J=6.0 Hz), 7.24-7.33 (m, 10H), 7.44-7.46 (m, 5H). MS (m/z): 396 [M]⁺

Example 4 Synthesis of chloroacetic acid2-(2-hydroxyethyldisulfanyl)ethyl ester (LI-1d)

To a solution of SL-1 (23 g, 150 mmol) in DCM (250 mL) at 0° C. wereadded TEA (10.12 g, 100 mmol) and chloroacetyl chloride (11.3 g, 100mmol) and stirred overnight at RT. The reaction mixture was concentratedand purified by column chromatography to afford 8.3 g (37%) of LI-1d.¹H-NMR (300 MHz, CDCl₃): δ 2.88 (t, 2H, J=5.7 Hz), 2.95 (t, 2H, J=6.6Hz), 3.89 (t, 2H, J=5.7 Hz), 4.09 (s, 2H), 4.47 (t, 2H, J=6.6 Hz).

Example 5 Synthesis of 2-((2-hydroxyethyl)dithio)ethyl nitrate (LI-2b)and 2,2′-bis(ethyl nitrate)disulfide (LI-3b)

These intermediates were synthesized in two steps as shown in Scheme 10.

Step 1: Synthesis of 2-((2-bromoethyl)dithio)ethanol (LI-2a) andbis(2-bromoethyl)disulfide (LI-3a): These compounds can be synthesizedvia bromination of SL-1 by a known bromination method. (For a suitablebromination method, see Fruniss, B. S. et al., Vogel's Text Book ofPractical Organic Chemistry, 5^(th) edition, Pearson Education,Singapore, 1989; pp 559-579). The following methods were explored:

Method 1: To a solution of SL-1 (15 g, 97.4 mmol) in DMF (50 mL) wasadded PPh₃ (25.5 g, 97.4 mmol) and cooled to 0° C. Bromine (3.33 mL,64.9 mmol) was added drop-wise and stirred at RT for 18 h. TLC of themixture showed the mono-bromo derivative LI-2a as the major product withonly trace amounts of dibromide LI-3a. The mixture was diluted withwater and extracted with EtOAc. After usual aqueous work-up andchromatographic purification, 3.65 g (26%) of LI-2a were obtained.¹H-NMR (300 MHz, CDCl₃): δ 1.82 (s, 1H), 2.88 (t, 2H, J=5.8 Hz), 3.08(t, 2H, J=7.90H), 3.63 (t, 2H, J=7.90 Hz), 3.90 (t, 2H, J=5.8 Hz).

Method 2: To a solution of SL-1 (40 g, 0.26 mol) in DCM (400 mL) at 0°C. was added a solution of PBr₃ (24.62 mL, 0.26 mol) in DCM (50 mL) andthe mixture was stirred at RT for 15 h. TLC indicated formation of LI-3aas the major product with trace amounts of LI-2a. The reaction wasquenched by the addition of water and extracted with DCM. After usualaqueous work-up and chromatographic purification, 33 g (45.3%) of LI-3awere obtained. ¹H-NMR (500 MHz, CDCl₃): δ 3.1-3.15 (m, 4H), 3.60-3.66(m, 4H). MS (Cl)⁺ m/z: 277.69 [M+H]⁺, 279.66. An alternative synthesisof LI-3a has been reported. (Sharma, M. et al, Bioorg. Med. Chem. Lett.,2004, 14, 5347-5350).

Method 3: To a cold suspension of SL-1 (20 g, 129 mmol) in DCM (400 mL)was added CBr₄ (42 g, 129 mmol) and stirred for 10 min. PPh₃ (34 g, 129mmol) was then added and stirred at RT for 14 h. The reaction mixturewas concentrated and the residue purified by column chromatography togive 13.5 g (52.3%) of LI-2a and 13.0 g (36%) of LI-3a. These compoundswere identical (by TLC, NMR and MS) to those obtained in Methods 1 and 2described above.

Synthesis of 2-((2-hydroxyethyl)dithio)ethyl nitrate (LI-2b): To asolution of LI-2a (2 g, 9.21 mmol) in acetonitrile (15 mL) was addedAgNO₃ (1.88 g, 11.05 mmol) portion-wise and the mixture was stirred atRT in the dark for 45 min. The reaction mixture was filtered throughcelite and the filtrate was concentrated. The residue, after usualaqueous work-up and chromatographic purification gave 1.46 g (74%) crudeLI-2b which was used for the next reaction without further purification.An analytical sample was obtained by chromatographic purification.¹H-NMR (300 MHz, CDCl₃): δ 2.89 (t, 2H, J=6.0 Hz), 2.98 (t, 2H, J=7.5Hz), 3.90 (t, 2H, J=6.0 Hz), 4.74 (t, 2H, J=7.5 Hz); MS (EI)⁺ (m/z): 199[M]⁺.

Synthesis of 2,2′-bis(ethyl nitrate)disulfide (LI-3b): AgNO₃ (8.01 g,47.12 mmol) was added portion-wise to a solution of LI-3a (6.0 g, 21.42mmol) in acetonitrile (40 mL) at RT in the dark and stirred for 30 min.The mixture was filtered through celite and the filtrate wasconcentrated in vacuo at 35° C. to afford 4.6 g (88%) of LI-3b, whichwas used without further purification. An analytical sample was obtainedby chromatographic purification (3-15% EtOAc in petroleum ether). ¹H-NMR(300 MHz, CDCl₃): δ 3.10 (t, 4H, J=6.7 Hz), 4.71 (t, 4H, J=6.7 Hz). MS(EI)⁺ m/z: 244 [M]⁺.

Example 6

Synthesis of tert-butyl 2-[(2-hydroxyethyl)dithio]ethylcarbamate(LI-2c): To a solution of cysteamine hydrochloride (15 g, 132 mmol) inMeOH (130 mL) at 0-5° C. was added TEA (37 mL, 264 mmol), followed by asolution of SL-1 (20.4 g, 132 mmol) in DCM (50 mL) and stirred at RT for6 h. The mixture, which contained the intermediate SL-2, was cooled and(Boc)₂O (63.4 g, 290.4 mmol) was added and stirred overnight. MeOH wasremoved under vacuum. After usual aqueous work-up and chromatographicpurification, LI-2c was obtained as a colorless oil (14.6 g, 44%).

The above linker intermediate can also be prepared by the followingmethod:

Step 1: TEA (37 ml, 264 mmol) and a solution of (Boc)₂O (48 g, 220 mmol)in DCM (100 mL) were added to a suspension of cystamine dihydrochloride(20 g, 88.8 mmol) in of DCM (300 mL) and stirred at RT for 15 h. Themixture was concentrated and the residue, after usual aqueous work-upand chromatographic purification, gave 30 g (96%) of tert-butyl2-({2-[(tert-butoxycarbonyl)amino]ethyl}dithio)ethylcarbamate as a whitesolid. ¹H-NMR (300 MHz, CDCl₃): δ 1.43 (s, 18H), 2.78 (t, 4H, J=6.3 Hz),3.44 (q, 4H, J=6.0 Hz), 5.00 (bs, 1H). MS (m/z): 353.18 [M+H]⁺, 375:24[M+Na]⁺.

Step 2: A solution of 2-mercaptoethanol (1.44 g, 18.5 mmol) in DCM (10mL) was added to a mixture of tert-butyl2-({2-[(tert-butoxycarbonyl)amino]ethyl}dithio)ethyl carbamate (5.0 g,14.2 mmol) and TEA (3.87 ml, 27.7 mmol) in DCM (30 mL) and stirredovernight at RT. After usual aqueous work-up and chromatographicpurification, 2.0 g (56%) of LI-2c was obtained. ¹H-NMR (300 MHz,CDCl₃): δ 1.43 (s, 9H), 2.79 (t, 2H, J=6.5 Hz), 2.87 (t, 2H, J=5.7 Hz),3.48 (q, 2H, J=6 Hz), 3.88 (t, 2H, J=5.5 Hz), 4.8 (bs, 1H). MS (m/z):254 [M+H]⁺, 276.13 [M+Na]⁺.

Removal of the Boc group of LI-2c was accomplished as described inExample 10 to afford the TFA salt, LI-2c.TFA.

Obviously, the linker intermediates LI-2b and LI-2c can also besynthesized by following the method outlined in Scheme 24.

Example 7

Synthesis of 2-Boc-aminoethyl-2′-methansulfonyloxyethyl disulfide(LI-2d): To an ice-cold solution of LI-2c (9 g, 35.52 mmol) in DCM (80mL) and TEA (9.9 mL, 71.04 mmol) was added methanesulfonyl chloride (4.2mL, 53.28 mmol). The reaction mixture was stirred at 0-5° C. for 45 min,then diluted with DCM. After usual aqueous work-up and chromatographicpurification, 13.38 g of LI-2d were obtained, which was pure enough forfurther use. ¹H-NMR (300 MHz, CDCl₃): δ 1.43 (s, 9H), 2.80 (t, 2H, J=6.4Hz), 2.98 (t, 2H, 5.7 Hz), 3.05 (s, 3H), 3.35-3.45 (m, 2H), 4.45 (t, 2H,J=6.7 Hz), 4.78 (br s, 1H).

Example 8

Synthesis of 2-Boc-aminoethyl-2′-bromoethyl disulfide (LI-2e): To asolution of LI-2d (13 g, 39.27 mmol) in acetone (100 mL) at RT was addedLiBr (6.82 g, 78.54 mmol) and stirred under reflux for 1 h. The reactionmixture was concentrated and the residue, after usual aqueous work-upand chromatographic purification, afforded 8.8 g (78%) of LI-2e. ¹H-NMR(300 MHz, CDCl₃): δ 1.44 (s, 9H), 2.80 (t, 2H, J=6.32 Hz), 3.06 (t, 2H,J=6.73 Hz), 3.44 (q, 2H), 3.61 (t, 2H, J=7.62 Hz), 4.87 (br s, 1H). MS(EI)⁺ m/z: 317 [M+H]⁺.

Example 9

Synthesis of 2-((2-Boc-aminoethyl)dithio)ethyl nitrate (LI-2f): To asolution of LI-2e (8 g, 25.3 mmol) in acetonitrile (80 mL) was addedAgNO₃ (5.16 g, 30.36 mmol) portion-wise and stirred at RT for 1 h in thedark. The mixture was filtered through celite and the filtrate wasconcentrated. The residue obtained was purified by column chromatographyto afford 6.34 g (84%) of LI-2f. ¹H-NMR (300 MHz, CDCl₃): δ 1.44 (s,9H), 2.80 (t, 2H, J=6.32 Hz), 3.06 (t, 2H, J=6.73 Hz), 3.44 (q, 2H),4.70 (t, 2H, J=7.62 Hz), 4.87 (br s, 1H). MS (EI)⁺ m/z: 299 [M+H]⁺.

The above linker intermediate was also prepared by the following method:TEA (3.56 g, 35.2 mmol) was added to a solution of cysteaminehydrochloride (2 g, 17.60 mmol) and LI-3b (4.29 g, 17.6 mmol) inmethanol (25 mL) at 0° C. and stirred at RT for 4 h. To the mixture,which contained the intermediate free amine (LI-5), a solution of(Boc)₂O (7.68 g, 35.2 mmol) and TEA (3.56 g, 35.2 mmol) in MeOH (10 mL)was added and the mixture was stirred overnight. The reaction mixturewas filtered through celite and evaporated to dryness. The residue waspurified by column chromatography to afford 0.380 g (7%) of LI-2f.

Example 10

Synthesis of 2-((2-Aminoethyl)dithio)ethyl nitrate. TFA salt (LI-5.TFA):To an ice-cold solution of LI-2f (2 g, 6.7 mmol) in DCM (20 mL) wasadded TFA (5 mL) and stirred at room temperature for 1 h. The mixturewas concentrated, the residue was triturated with ether and concentratedto remove traces of TFA and finally dried to afford LI-5.TFA, which wasused as such in further reactions.

The above linker intermediate LI-5.TFA was also synthesized as describedbelow: TEA (3.56 g, 35.2 mmol) was added drop-wise to a solution ofcysteamine hydrochloride (2 g, 17.60 mmol) and LI-3b (4.29 g, 17.6 mmol)in MeOH (25 mL) at 0° C. and stirred at RT for 4 h. The mixture wascooled to 0° C. and a solution of (Boc)₂O (7.68 g, 35.2 mmol) in MeOH(10 mL) was added, followed by TEA (3.56 g, 35.2 mmol), and stirredovernight at RT. The reaction mixture was filtered through celite andthe filtrate concentrated. The residue was purified by columnchromatography to afford 0.38 g (7.25%) of LI-2f, which was identical(TLC and ¹H-NMR) to that obtained in Example 9. Removal of the Boc groupfrom LI-2f to give LI-5.TFA was accomplished as described in Example 10.

Example 11

Synthesis of methyl [(2-hydroxyethyl)dithio]acetate (L3I2a): Methylmercaptoacetate (10.32 g, 97.4 mmol) was added to a solution of SL-1(10.0 g, 64.93 mmol) in DCM (150 mL) at RT, followed by TEA (18 mL, 129mmol) and the mixture was stirred overnight at RT. After usual aqueouswork-up and chromatographic purification, 2.7 g (22.9%) of L3I2a wereobtained. ¹H-NMR (300 MHz, CDCl₃): δ 2.95 (t, 2H, J=2.5 Hz), 3.49 (s,2H), 3.76 (s, 3H), 3.86 (q, 2H, J=5.64). MS (m/z): 182 [M+H]⁺.

Example 12

Synthesis of prodrug I-C1-PD10: This prodrug was synthesized asdescribed in Scheme 11, Method B. Thus, TEA (0.73 mL, 10 mmol) was addedto a suspension of cetirizine dihydrochloride (2.0 g, 4.68 mmol) in DCM(50 mL), followed by a solution of SL-1 (0.72 g, 4.67 mmol), DCC (1.13g, 5.47 mmol) and DMAP (0.112 g, 1 mmol) and stirred at RT for 15 h. Themixture was concentrated and the residue, after usual aqueous work-upand chromatographic purification, gave 0.44 g (19%) of I-C1-PD10. ¹H-NMR(300 MHz, CDCl₃): δ 2.50 (bs, 4H), 2.80 (bs, 6H), 2.87 (t, 2H, J=6.09Hz), 2.94 (t, 2H, J=7.32 Hz), 3.75 (m, 2H), 3.86 (t, 2H, J=6.12 Hz),4.13 (s, 2H), 4.24 (s, 1H), 4.40 (t, 2H, J=6.09 Hz) and 7.22-7.35 (m,9H). MS (m/z): 527 [M+H]⁺.

Example 13

Synthesis of prodrug I-C1-PD6: Step 1: To a suspension of aspirin (3 g,16.65 mmol) in benzene (25 mL) and DMF (2 drops) at 0-5° C. was addedoxalyl chloride (1.7 mL, 19.98 mmol) in benzene (5 mL). The reactionmixture was refluxed at 85° C. for 2 h, cooled to RT and concentrated togive a yellow oil.

Step 2: The yellow oil was dissolved in benzene (30 mL), silver cyanate(2.99 g, 19.98 mmol) was added and the mixture was refluxed for 1 h inthe dark.

Step 3: The reaction mixture was cooled to RT, and a solution of SL-1(2.56 g, 16.65 mmol) in benzene (5 mL). The reaction mixture was stirredfor 1 h, filtered through celite, concentrated and purified by columnchromatography to afford 2.24 g (54%) of I-C1-PD6. ¹H NMR (CDCl₃, 300MHz): δ 2.12 (s, 3H), 2.83-2.91 (m, 4H), 3.84 (t, J=5.9 Hz, 2H), 4.27(t, J=5.16 Hz, 2H); 6.20 (br s, 1H), 7.06 (d, J=8.21 Hz, 1H), 7.19 (t,J=7.55 Hz, 1H), 7.59 (t, J=7.24 Hz, 1H), 7.97 (d, J=6.82 Hz, 1H). MS:m/z 360.06 [M+H]⁺, 377.05 [M+NH₄]⁺, 382.01 [M+Na]⁺, 357.96 [M−H]⁻.

Example 14

Synthesis of prodrug I-C1-PD11: To a solution of SL-1 (7 g, 45.45 mmol)and valproic acid (7.85 g, 54.5 mmol) in DCM (80 mL) was added DCC(11.26 g, 54.5 mmol), followed by DMAP (6.65 g, 54.5 mmol), and theresulting suspension was stirred at RT for 18 h. After usual aqueouswork-up and chromatographic purification, 2.82 g (22%) of I-C1-PD11 wereobtained as a colorless oil. ¹H NMR (CDCl₃, 300 MHz): δ 0.86-0.93 (m,6H), 1.22-1.29 (m, 8H), 1.32-1.59 (m, 4H), 2.37 (m, 1H), 3.89 (t, 2H,J=5.7 Hz), 4.35 (t, 2H, J=6.5 Hz).

Example 15

Synthesis of prodrug I-C1-PD13: To a solution of valpromide (5 g, 34.9mmol) in DCE (50 mL) was added oxalyl chloride (3.7 mL, 41.88 mmol) at0° C. and refluxed for 16 h. The mixture was added to a solution of SL-1(10.76 g, 69.8 mmol) in DCE (80 mL) and stirred overnight at RT. Afterusual aqueous work-up and chromatographic purification, 5.01 g (44%) ofI-C1-PD13 were obtained as a colorless oil. ¹H NMR (CDCl₃, 300 MHz): δ0.89 (t, 6H, J=7.21 Hz), 1.23-1.66 (m, 9H), 2.90 (t, 2H, 5.82 Hz), 2.97(t, 2H, J=6.46 Hz), 3.90 (t, 2H, J=5.82 Hz), 4.44 (t, 2H, J=6.48 Hz),7.61 (br s, 1H)

Example 16

Synthesis of prodrug I-C1-PD14: To a cold solution of diphosgene (0.9mL, 7.14 mmol) in DCM (5 mL) was added a solution of I-C1-PD11 (1 g,3.57 mmol) and DIPEA (1.9 mL, 10.71 mmol) in DCM (5 mL). The reactionmixture was stirred at RT for 30 min. DCM and excess phosgene wereremoved under vacuum and the resulting solid was dissolved in DCM (5mL). To it was added a suspension of methanesulfonamide (0.41 g, 4.284mmol) and DIPEA (1.9 mL, 10.71 mmol) in DCM (5 mL) at 0-5° C. and themixture was stirred overnight at RT. After usual aqueous work-up andchromatographic purification, 1.1 g (77%) of I-C1-PD14 were obtained asa white solid. ¹H NMR (CDCl₃, 300 MHz): δ 0.89 (t, 6H, J=7.22 Hz),1.27-1.63 (m, 8H), 2.34-2.43 (m, 1H), 2.90 (t, 2H, J=7.0 Hz), 2.96 (t,2H, J=6.13 Hz), 3.30 (s, 3H), 4.36 (t, 2H, J=6.98 Hz), 4.45 (t, 2H,J=6.14 Hz). MS: (ES⁺) m/z 402 [M+H]⁺, 419 [M+NH₄]⁺, 424 [M+Na]⁺, 440[M+K]⁺; (ES⁻) 401 [M−H]⁻.

Example 17 Synthesis of Prodrug I-A1-PD1

This prodrug was synthesized as shown in Scheme 14, Method B. Thus, to asolution of amlodipine (18.75 g, 45.86 mmol) in DCM (100 mL) at 0° C.was added triphosgene (4.62 g, 15.59 mmol) followed by TEA (7.71 g,76.35 mmol) in DCM (10 mL) and stirred at RT for 3 h. To this was addeda solution of LI-1a (9.0 g, 48.86 mmol) and TEA (4.63 g, 45.86 mmol) inDCM (10 mL) at 0° C. and stirred at RT for 3 d. The mixture wasconcentrated and the residue purified by column chromatography to yield23 g (79.5%) of I-A1-PD1. ¹H-NMR (300 MHz, CDCl₃): δ 1.16 (t, 3H, J=7.5Hz), 2.05 (s, 3H), 2.34 (s, 3H), 2.86-2.94 (m, 4H), 3.43-3.45 (m, 2H),3.59-3.62 (m, 5H), 4.0-4.35 (m, 4H), 4.30-4.35 (m, 4H), 4.69 (q, 2H,J=15 Hz), 5.20 (bs, 1H), 5.38 (s, 1H), 7.01-7.34 (m, 4H). MS (m/z): 631[M+H]⁺, 653 [M+Na]⁺.

Example 18

Synthesis of prodrug I-A1-PD2: To a solution of I-A1-PD1 (23.0 g, 36.45mmol) in MeOH (250 mL) at 0° C. was added a solution of K₂CO₃ (7.54 g,54.67 mmol) in water (55 mL) and stirred for 10 min. The mixture wasconcentrated and purified by column chromatography to afford 18 g(83.8%) of the intermediate I-A1-PD2. ¹H-NMR (300 MHz, CDCl₃): δ 1.16(t, 3H, J=6 Hz), 2.35 (s, 3H), 2.84-2.88 (t, 2H, J=6 Hz), 2.90-2.94 (t,2H, J=6 Hz), 3.44 (bs, 2H), 3.59-3.61 (bs, 5H), 3.84-3.91 (m, 2H),4.0-4.03 (q, 2H, J=3.11 Hz), 4.33 (bs, 2H), 4.69 (q, 2H, J=15 Hz), 5.28(bs, 1H), 5.37 (s, 1H), 7.12-7.36 (m, 4H). MS (ES⁺): m/z 589 [M⁺], 611[M+Na]⁺.

Example 19

Synthesis of prodrug I-A1-PD3: To a suspension of lamotrigine (13.09 g,51.02 mmol) in toluene (100 mL) at 110° C. was added a solution ofLI-1xy (synthesized from LI-1a and CDI, as described in Scheme 10)(16.27 g, 56.12 mmol) in THF (50 mL) and stirred at 110° C. overnight.The reaction mixture was purified by column chromatography to give 6.0 g(24%) of I-A1-PD3 as a white solid. ¹H NMR (CD₃OD, 300 MHz) δ 2.04, (s,3H), 2.96-3.02 (m, 4H), 4.30-4.35 (m, 2H), 4.45 (t, 2H), 7.38-7.45 (m,2H), 7.67-7.69 (m, 1H). MS: (ES⁺) m/z 477.9 (M+H)⁺, 499.9 (M+Na)⁺.

Example 20

Synthesis of prodrug I-A1-PD4: To a solution of I-A1-PD3 (2 g, 4.18mmol) in MeOH (15 mL) and THF (5 mL) at 0° C. was added a solution ofK₂CO₃ (0.886 g, 6.276 mmol) in water (5 mL) and stirred at 0° C. for 3h. After usual aqueous work-up and chromatographic purification, 1.1 g(60%) of I-A1-PD4 were obtained as a white solid. ¹H NMR (DMSO d₆, 300MHz): δ 2.75-2.82 (m, 2H), 2.96-3.0 (m, 2H), 3.0 (s, 1H), 3.6 (t, 2H,J=6.3 Hz), 4.30 (t, 2H, J=6.6 Hz) 7.38-7.49 (m, 2H), 7.72-7.75 (m, 1H).MS: (ES+) m/z 436 (M+H)⁺, 457 (M+Na)⁺.

Example 21

Synthesis of prodrug I-A1-PD5: To a solution of diphosgene (0.99 mL,8.24 mmol) in DCM (3 mL) at 0° C. was added a solution of L3I2a (0.5 g,2.74 mmol) and Hünig's base (2.39 mL, 13.73 mmol) in DCM (3 mL). Themixture was stirred at 0° C. for 30 min and concentrated to yield theintermediate L3I3a as a light-yellow semi-solid. A solution of a mixtureof gabapentin ethyl ester hydrochloride (0.77 g, 3.29 mmol) and Hünig'sbase (1.7 mL, 9.79 mmol) in DCM (6 mL) was added to the intermediateL3I3a at RT and stirred for 15 h. After usual aqueous work-up andchromatographic purification, 0.34 g (30%) of I-A1-PD5 were obtained asa yellow oil. ¹H NMR (CDCl₃, 300 MHz): δ 1.26 (t, 3H, J=6 Hz), 1.22-1.51(m, 10H), 2.26 (s, 2H), 2.96 (t, 2H, J=6 Hz), 3.18 (d, 2H, J=6 Hz), 3.49(s, 2H), 3.82 (s, 3H), 4.09 (q, 2H, J=6 Hz), 4.29 (t, 2H, J=6 Hz), 5.39(bs 1H). MS: (ES⁺) m/z 408 (M+H)⁺, 430 (M+Na)⁺; (ES⁻) m/z 406 (M−H)⁻.

Example 22

Synthesis of prodrug I-A1-PD6: To a solution of I-A1-PD8 (1.0 g, 2.63mmol) in DCM (3 mL) at RT was added CDI (0.46 g, 2.89 mmol) and stirredfor 15 h. A suspension of serine methyl ester hydrochloride (0.61 g,3.95 mmol) in DCM (4 mL) and TEA (1.1 mL, 7.90 mmol) was added andstirring continued for 15 h. After usual aqueous work-up andchromatographic purification, 0.706 g (51%) of I-A1-PD6 were obtained asa colorless oil. ¹H NMR (CDCl₃, 300 MHz): δ 1.25 (t, 3H, J=7.1 Hz),1.35-1.51 (m, 10H), 2.28 (s, 2H), 2.91-2.98 (m, 4H), 3.16 (d, 2H, J=9Hz), 3.78 (s, 3H), 3.94-4.38 (m, 9H), 5.5 (bs, 1H), 6.0 (bs, 1H). MS:(ES)⁺: m/z 525 (M+H)⁺, 547 (M+Na)⁺. (ES)⁻: m/z 523 (M−H)⁺.

Example 23

Synthesis of prodrug I-A1-PD7: To a solution of I-A1-PD8 (86 mg, 0.22mmol) in DCM (9 mL) at RT was added CDI (40 mg, 0.24 mmol) and stirredfor 15 h, after which a solution of dimethyl glutamate (80 mg, 0.45mmol) and TEA (0.06 mL, 0.45 mmol) was added and stirred for 2 d. Afterusual aqueous work-up and chromatographic purification, 97 mg (74%) ofI-A1-PD7 were obtained as a colorless oil. ¹H NMR (CDCl₃, 300 MHz): δ1.25 (t, 3H, J=7.13 Hz), 1.36-2.5 (m, 16H), 2.93 (t, 4H, J=6.46 Hz),3.19 (d, 2H, J=6.67), 3.67 (s, 3H), 3.74 (s, 3H), 4.12 (q, 2H, J=7.13Hz), 4.25-4.44 (m, 5H), 5.4 (bs, 1H), 5.65 (bs, 1H). MS: (ES⁺) m/z 581(M+H)⁺, 603 (M+Na)⁺; (ES⁻) m/z 571 (M−H)⁻.

Example 24

Synthesis of prodrug I-A1-PD9: To a suspension of gabapentin (10 g, 58.4mmol) in THF (100 mL) at 0° C. was added 1N NaOH (70 mL), followed by(Boc)₂O. The mixture was stirred at RT for 15 h. After washing withdiethyl ether (100 mL×2), the aqueous layer was acidified with solidKHSO₄ and extracted with EtOAc (100 mL×2). Organic extracts were washedwith brine (100 mL), dried over Na₂SO₄ and concentrated to afford 10.41g (68%) of boc-protected gabapentin as a white solid.

A mixture of boc-protected gabapentin (5.0 g, 18.45 mmol) and CDI (3.59g, 22.14 mmol) in DCM (75 mL) was stirred for 15 h. The mixture wasconcentrated and dissolved in acetonitrile (50 mL), followed by theaddition of 30% aqueous solution of ammonia (50 mL) and stirred for 1.5h at RT. After usual aqueous work-up, 4.5 g (90%) of boc-protectedgabapentin-amide were obtained as a white solid.

To a solution of boc-protected gabapentin-amide (2.59 g, 9.61 mmol) inDCM (12 mL) at 0° C. was added solution of TFA (4 mL) in DCM (4 mL) andstirred for 2.5 h at RT. The mixture was concentrated and dissolved inDCM (20 mL). This was treated successively with Hunig's base (6.7 mL,38.46 mmol) and LI-1a (1.45 g, 7.39 mmol), and stirred at RT for 3 h.After usual aqueous work-up and chromatographic purification, 1.19 g(41%) of I-A1-PD9 were obtained as a yellow oil. ¹H NMR (CDCl₃, 300MHz): δ 1.28-1.48 (m, 10H), 2.06 (s, 3H), 2.15 (s, 2H), 2.91 (t, 4H,J=6.0 Hz), 3.23 (d, 2H, J=6.0 Hz), 4.28-4.38 (m, 4H), 5.7 (bs, 1H). MS:(ES)⁺ m/z 393 (M+H)⁺; (ES)⁻ m/z 392 (M−H)⁻.

Example 25

Synthesis of prodrug I-A1-PD10: A mixture of I-A1-PD8 (1.0 g, 2.63 mmol)and CDI (0.469 g, 2.89 mmol) in DMF (3 mL) was stirred for 12 h, afterwhich N,N′ dimethylethylenediamine (0.56 mL, 5.26 mmol) and DMAP (0.32g, 2.63 mmol) was added. The mixture was stirred for 4 h. After usualaqueous work-up and chromatographic purification, 0.763 g (59%) ofI-A1-PD10 were obtained as a yellow oil. ¹H NMR (CDCl₃, 300 MHz): δ 1.25(t, 3H, J=6.0 Hz), 1.28-1.53 (m, 10H), 2.24 (s, 6H), 2.29 (s, 2H), 2.42(t, 2H, J=6.0 Hz), 2.92 (t, 4H, J=6.0 Hz), 3.20 (d, 2H, J=6.0 Hz), 3.26(q, 4H, J=6.0 Hz), 4.13 (q, 2H, J=7.0 Hz), 4.31 (t, 4H, J=6.0 Hz), 7.26(bs, 1H). MS: (ES)⁺ m/z 494 (M+H)⁺, 516 (M+Na)⁺; (ES)⁻ m/z 492 (M−H)⁻.

Example 26

Synthesis of prodrug I-A1-PD11: A mixture of LI-1a (2.0 g, 10.20 mmol)and CDI (1.98 g, 12.24 mmol) in DCM (12 mL) was stirred for 2 h andconcentrated. The residue was dissolved in acetonitrile, and asuspension of gabapentin (2.62 g, 15.30 mmol) in saturated NaHCO₃ (15mL) was added. The mixture was stirred at RT for 15 h. Acetonitrile wasremoved by distillation and the basic aqueous portion was washed withdiethyl ether (100 mL×2). The aqueous layer was acidified using 2N HCland extracted in EtOAc (60 mL×3). The organic layer was concentrated andthe residue was purified by chromatographic purification, 1.76 g (43%)of I-A1-PD11 were obtained as a colorless oil. ¹H NMR (CDCl₃, 300 MHz):δ 1.27-1.68 (m, 10H), 2.07 (s, 3H), 2.31 (s, 2H), 2.92 (t, 4H, J=6.0Hz), 3.22 (d, 2H, J=9.0 Hz), 4.31-4.35 (m, 4H), 5.43 (bs, 1H). MS: (ES)⁻m/z 392 (M−H)⁻.

Example 27

Synthesis of prodrug I-A1-PD13: This prodrug was synthesized as shown inScheme 12, Method B. Thus, to a solution of diphosgene (7.02 mL, 58.18mmol) in DCM (20 mL) at 0° C. was added a solution of LI-1a (5.71 g,29.09 mmol) and Hünig's base (25.3 mL, 145.45 mmol) in DCM (30 mL) andstirred at RT for 40 min. The mixture was concentrated and a mixture ofgabapentin ethyl ester hydrochloride (7.546 g, 32 mmol) and Hünig's base(11.15 mL, 64 mmol) in DCM (50 mL) was added and stirred overnight.Reaction mixture was concentrated and, after usual aqueous work-up andcolumn chromatography, 8.42 g (67%) of I-A1-PD13 were obtained. ¹H NMR(CDCl₃, 300 MHz): δ 1.22 (t, 3H, J=7.3 Hz), 1.27-1.68 (m, 10H), 2.06 (s,3H), 2.27 (s, 2H), 2.91 (t, 4H, J=6.6 Hz), 3.19 (d, 2H, J=6.7 Hz),4.08-4.15 (q, 2H, J=7.1 Hz), 4.27-4.34 (q, 4H, J=6.4 Hz), 5.4 (bs, 1H).MS: m/z 422 [M+H]⁺, 444 [M+Na]⁺.

Example 28

Synthesis of prodrug I-A1-PD8: To an ice-cold solution of I-A1-PD13 (8.0g, 18.98 mmol) in MeOH (30 mL) was added a solution of K₂CO₃ (5.24 g,37.96 mmol) in water (38 mL). After 15 min, the mixture wasconcentrated. After usual aqueous work-up, 5.0 g (69%) of I-A1-PD8 wereobtained. ¹H NMR (CDCl₃, 300 MHz): δ 1.25 (t, 3H, J=7.11 Hz), 1.30-1.71(m, 10H), 2.87-2.94 (m, 4H), 2.27 (s, 2H), 3.18 (d, 2H, J=6.6 Hz), 3.87(t, 2H, J=5.7 Hz), 4.09-4.16 (q, 2H, J=7.12 Hz), 4.31 (t, 2H, J=6.51Hz), 5.44 (bs, 1H). MS: m/z 380 [M+H]⁺, 402 [M+Na]⁺.

Example 29

Synthesis of prodrug I-A1-PD12: To a solution of diphosgene (1.91 mL,15.81 mmol) in DCM (20 mL) at 0° C. was added a solution of I-A1-PD8 (4g, 10.54 mmol) and Hünig's base (5.5 mL, 31.62 mmol) in DCM (30 mL). Themixture was stirred at RT for 40 min, cooled to 0-5° C., and dry ammoniagas was passed through it for 30 min. Reaction mixture was concentratedand, after usual aqueous work-up, 5.3 g (91%) of I-A1-PD12 wereobtained. ¹H NMR (CDCl₃, 300 MHz): δ 1.23 (t, 3H, J=7.1 Hz), 1.27-1.79(m, 10H), 2.28 (s, 2H), 2.91-3.03 (m, 4H), 3.19 (d, 2H, J=6.7 Hz), 4.12(q, 2H, J=7.1 Hz), 4.31 (t, 4H, J=6.4 Hz), 5.4 (t, 1H, J=6.0 Hz). MS:m/z 423 [M+H]⁺, 446 [M+Na]⁺.

Example 30

Synthesis of prodrug I-A1-PD14: Ethyl chloroformate (0.86 g, 7.9 mmol)was added to a solution of 3-carbamoylmethyl-5-methylhexanoic acid (M.S. Hoekstra et al., Org. Proc. Res. Dev. 1997, 1, 26-38) (1.0 g, 5.3mmol) in THF (6 mL) at −10° C., followed by TEA (2.4 mL, 17.0 mmol) andthe mixture was stirred at −10° C. for 30 min. A solution of NaN₃ (1.73g, 26.6 mmol) in water (10 mL) was added and stirred for 2 h at −10° C.The reaction mixture was brought to RT and extracted with EtOAc (3×25mL), washed with water (2×25 mL), dried over Na₂SO₄ and concentrated.Toluene (20 mL) was added to the residue and refluxed for 6 h. Aftercooling to RT, a solution of and SL-1 (825 mg, 5.3 mmol) in DCM (10 mL)was added and stirred at RT for 14 h. After usual aqueous work-up andchromatographic purification, 318 mg (17%) of I-A1-PD14 were obtained asa colorless oil. ¹H NMR (300 MHz, CDCl₃): δ 0.89-0.95 (m, 6H), 1.25-1.29(m, 2H), 1.62-1.71 (m, 1H), 2.04-2.1 (m, 1H), 2.38 (d, J=5.2 Hz, 2H),2.87-2.95 (m, 4H), 3.05-3.36 (m, 2H), 3.88 (t, J=5.7 Hz, 2H), 4.34 (t,J=6.2 Hz, 2H), 5.06 (br s, 1H). MS: m/z 338 [M]⁺.

Example 31

Synthesis of prodrug I-A1-PD15Ba: To a solution of I-A1-PD4 (0.350 g,0.802 mmol) in DMF (3 mL) at RT was added CDI (0.195 g, 1.204 mmol) andstirred at RT for 3 h. This mixture was added to a suspension ofmethanesulphonamide (0.304 g, 3.2 mmol) in DMF (4 mL) and NaH (0.153 g,3.2 mmol) at 0° C. and stirred at RT for 4 h. The reaction was quenchedwith ice and, after usual aqueous work-up and chromatographicpurification, 0.12 g (26%) of I-A1-PD15Ba were obtained as a whitesolid. ¹H NMR (CDCl₃+CD₃OD, 300 MHz): δ 2.83-2.90 (m, 4H), 3.10 (s, 3H),4.26-4.36 (m, 4H), 7.19-7.28 (m, 2H), 7.48-7.51 (m, 1H). MS: (ES⁺) m/e556.96 (M+H)⁺, 578.92 (M+Na)⁺.

Example 32

Synthesis of prodrug I-A1-PD18: CDI (4 g, 24.7 mmol) was added to asolution of LI-2c (4 g, 15.8 mmol) in THF (30 mL) and stirred at RT for2 h. Then, a solution of gabapentin (4 g, 23.4 mmol) in 20% NaHCO₃solution (10 mL) was added and stirred overnight at RT. The reactionmixture was neutralized with 0.5N HCl (pH ˜4), extracted with EtOAc(4×40 mL), dried over Na₂SO₄, concentrated and purified by columnchromatography to afford 4.7 g (66%) of I-S12-PD2 as a colorless oil. ¹HNMR (300 MHz, CDCl₃): δ 1.45-1.49 (br s, 19H), 2.35 (s, 2H), 2.80-2.97(m, 4H), 3.24 (d, J=5.7 Hz, 2H), 3.46 (m, 2H) 4.33 (t, J=5.7 Hz, 2H),5.0 (br s, 1H), 5.71 (br s, 1H). MS: (m/z) [ES]⁻ 449.1 [M−H]⁺; [ES]⁺451.2 [M+H]⁺.

EtOAc saturated with HCl gas (5 mL) was added to I-S12-PD2 (0.55 g, 1.22mmol) and stirred at RT for 10 h. Solvent was removed under reducedpressure and purified by preparative HPLC to give 425 mg (90%) ofI-A1-PD18 as a colorless liquid. ¹H NMR (300 MHz, CD₃OD): δ 1.52 (br s,10H), 2.4 (s, 2H), 2.98-3.09 (m, 4H), 3.27-3.34 (m, 2H), 3.61 (s, 2H),4.5 (t, J=6.0 Hz, 2H). MS: [ES]⁺ m/z 351.0 [M+H]⁺.

Example 33

Synthesis of prodrug I-A2-PD1: To a solution of levetiracetam (1.0 g,5.87 mmol) in DCE (20 mL) and DCM (4 mL) was added oxalyl chloride (0.61mL, 7.05 mmol), and heated at 70° C. for 8 h. Reaction mixture wascooled and added to a solution of SL-1 (1.81 g, 11.75 mmol) in DCM (15mL) and stirred at RT overnight. After chromatographic purification,1.13 g (41%) of I-A2-PD1 were obtained. ¹H NMR (CDCl₃, 300 MHz): δ(ppm): 0.87 (t, J=7.3 Hz, 3H), 1.84-2.04 (m, 4H), 2.41 (t, J=6.9 Hz,2H), 2.69 (bs, 1H), 2.87-2.95 (m, 4H), 3.02-3.11 (m, 1H), 3.65-3.75 (m,1H), 3.85-3.95 (m, 2H), 4.06-4.12 (m, 1H), 4.34-4.41 (m, 2H), 8.69 (bs,1H). MS: (ES⁺): m/z 351.0 [M+H]⁺; 372.9 [M+Na]⁺.

Example 34

Synthesis of prodrug I-A3-PD1: To a solution of I-S13-PD1 (which wassynthesized as described in Example 37, Step 2) (215 mg, 0.292 mmol) andtriisopropylsilane (60 μL) in 0.75 mL of DCM was added 20% TFA in DCM(0.5 mL) and stirred at RT for 90 min. The mixture was concentrated andthe residue purified by column chromatography to give 65 mg (46%) ofI-A3-PD1. ¹H-NMR (300 MHz, CDCl₃): δ 2.51 (s, 3H), 2.85-2.92 (m, 4H),3.87 (t, 2H, J=4.5 Hz), 4.37 (t, 2H, J=6.0 Hz), 7.25-7.43 (m, 7H), 8.01(d, 2H, J=3.0 Hz). MS (m/z): 493 [M−H]⁻, 517 [M+Na]⁺.

Example 35

Synthesis of prodrugs I-A3-PD3a and I-A3-PD3b: Step 1: DSC (210 mg,0.824 mmol) and TEA (0.230 mL, 1.64 mmol) were added to a solution ofmethyl [(2-hydroxyethyl)dithio]acetate (100 mg, 0.549 mmol) inacetonitrile (1 mL) at 0° C. and stirred at RT for 3 h. The mixture wasconcentrated and the residue dissolved DCM. Usual aqueous work-up andchromatographic purification gave the crude intermediate.

Step 2: TEA (24 mg, 0.236 mmol) and DMAP (13 mg) were added to a mixtureof valdecoxib (62 mg, 0.195 mmol) and the product obtained from step 1above in THF (1 mL) and stirred at RT for 3 d. The mixture wasconcentrated and the residue dissolved in EtOAc. After usual aqueouswork-up and chromatographic purification, 53 mg (52%) of I-A3-PD3aobtained. ¹H-NMR (300 MHz, CDCl₃): δ 2.51 (s, 3H), 2.97 (t, 2H, J=6.0Hz), 3.48 (s, 2H), 3.76 (s, 3H), 4.37 (t, 2H, J=6.0 Hz), 7.33-7.40 (m,7H), 8.03-8.12 (m, 2H). MS (m/z): 521 [M−H]⁻.

Step 3: The above material was converted to the corresponding mono-,and/or di-sodium salt forms I-A3-PD3b by using standard methods. Thus,to a cold solution of the above compound (150 mg, 0.287 mmol) in THF (1mL) was added 1M LiOH solution (28 mg in 1 mL water) and stirredovernight at RT. The mixture was concentrated, the residue diluted withwater, acidified with 1N HCl (˜3 ml, pH ˜3) and extracted with EtOAc.After usual aqueous work-up and chromatographic purification, 20 mg(13%) of product were obtained. ¹H-NMR (300 MHz, CDCl₃): δ 2.49 (s, 3H),2.70-2.89 (m, 4H), 4.23-4.33 (m, 2H), 7.28-7.38 (m, 7H), 8.01-8.03 (m,2H).

Example 36

Synthesis of prodrug I-A3-PD4: This prodrug was synthesized as describedin Scheme 13, Method B.

Step 1: Synthesis of Intermediate LI-8:

CDI (1.65 g, 10.19 mmol) was added to a solution of LI-1a (2.0 g, 10.19mmol) in DMF (10 mL) and stirred at RT for 3 h.N,N-Dimethylethylenediamine (1.2 mL, 11.12 mmol) was added and stirredfor 2 h. The mixture was concentrated and the residue taken up in EtOAc.After usual aqueous work-up and chromatographic purification, 1.3 g(41%) LI-8 were obtained. ¹H-NMR (300 MHz, CDCl₃): δ 2.07 (s, 3H), 2.31(bs, 6H), 2.51 (t, 2H, J=6.0 Hz), 2.91 (t, 4H, J=6.0 Hz), 3.31 (q, 2H,J=6.0 Hz), 4.28-4.34 (m, 4H), 5.52 (bs, 1H). MS (m/z): 333 [M+Na]⁺.

Step 2: Synthesis of intermediate LI-9: To a solution of LI-8 (1.3 g,4.18 mmol) in MeOH (7 mL) was added a 1.25M solution of K₂CO₃ (5 mL) andstirred at RT for 1 h. The mixture was concentrated and the residue wastaken up in DCM. After usual aqueous work-up, 1.02 g (91%) of productwere obtained. ¹H-NMR (300 MHz, CDCl₃): δ 2.29 (s, 6H), 2.54 (t, 2H,J=6.0 Hz), 2.86-2.99 (m, 4H), 3.33 (q, 2H, J=5.0 Hz), 3.86 (t, 2H, J=6.0Hz), 4.31 (t, 2H, J=6.0 Hz), 5.71 (bs, 1H). MS (m/z): 269 [M+H]⁺. Thisproduct was used as such in the next step.

Step 3: Synthesis of intermediate LI-10: A solution of LI-9 (1.02 g,3.80 mmol) in acetonitrile (10 mL) was added to a cold solution of DSC(1.46 g, 5.70 mmol) in acetonitrile (50 mL) followed by TEA (1.58 ml,11.40 mmol), and stirred overnight at RT. The mixture was concentratedand the residue was taken up in DCM. After usual aqueous work-up, 1.33 g(85%) of LI-10 were obtained.

Step 4: Synthesis of I-A3-PD4: TEA (0.194 mL, 1.39 mmol) and DMAP (73mg, 0.6 mmol) were added to a solution of LI-10 (1.33 g, 3.24 mmol) andvaldecoxib (364 mg, 1.16 mmol) in THF (6 mL) and stirred at RT for 5 d.The mixture was concentrated and the residue was taken up in DCM. Afterusual aqueous work-up and chromatographic purification, 177 mg (12%) ofLI-10 were obtained. ¹H-NMR (300 MHz, CDCl₃): δ 2.46 (s, 3H), 2.85-2.95(m, 10H), 3.28 (t, 2H, J=6.0 Hz), 3.65 (q, 2H, J=3.0 Hz), 4.22-4.28 (m,4H), 7.22-7.41 (m, 7H), 7.94 (d, 2H, J=9.0 Hz). MS (m/z): 609 [M+H]⁺.This product was converted to water-soluble hydrochloride salt formusing standard methods.

Example 37

Synthesis of prodrug I-A3-PD5: This prodrug was synthesized as shown inScheme 13, Method B.

Step 1: Synthesis of Prodrug Intermediate LI-1xy:

A solution of LI-1c (1.0 g, 2.52 mmol) in acetonitrile (10 mL) was addedto a solution of DSC (0.96 g, 3.78 mmol) in acetonitrile (20 mL) andstirred for 10 min. After cooling to 0° C., TEA (1 ml, 7.57 mmol) wasadded and stirred at RT for 3.5 h. The solution was concentrated and theresidue was taken up in DCM. After usual aqueous work-up, the crudeproduct obtained was used as such in the next step.

Step 2: Synthesis of prodrug intermediate I-S13-PD1: A mixture ofvaldecoxib (280 mg, 0.892 mmol), DMAP (56 mg, 0.5 mmol) and TEA (150 μL,1.06 mmol) in THF (5 mL) was stirred at RT for 4.5 d. The mixture wasconcentrated and the residue dissolved in EtOAc. After usual aqueouswork-up and chromatographic purification, 354 mg (54%) of I-S13-PD1 wereobtained. ¹H-NMR (300 MHz, CDCl₃): δ 2.47 (s, 3H), 3.32-3.41 (m, 4H),4.28 (t, 2H, J=6.0 Hz), 4.47 (t, 2H, J=6.0 Hz), 7.20-7.61 (m, 22H), 8.00(d, 2H, J=9.0 Hz). MS (m/z): 736 [M−H]⁻.

Step 3: Synthesis of intermediate I-A3-PD1: To a solution of I-S13-PD1(215 mg, 0.292 mmol) and triisopropylsilane (60 μL) in 0.75 ml of DCMwas added 20% TFA in DCM (0.5 mL) and stirred at RT for 90 min. Themixture was concentrated and the residue purified by columnchromatography to give 65 mg (46%) of I-A3-PD1. ¹H-NMR (300 MHz, CDCl₃):δ 2.51 (s, 3H), 2.85-2.92 (m, 4H), 3.87 (t, 2H, J=4.5 Hz), 4.37 (t, 2H,J=4.5 Hz), 7.25-7.43 (m, 7H), 8.01 (d, 2H, J=3.0 Hz). MS (m/z): 493[M−H]⁻, 517 [M+Na]⁺.

Step 4: Synthesis of I-A3-PD5-Me-ester: CDI (40 mg, 0.243 mmol) wasadded to a solution of I-A3-PD1 (100 mg, 0.202 mmol) in DMF (0.5 mL) andstirred at RT for 2.5 h. To this were added a solution of dimethylglutamate (53 mg, 0.303 mmol) in DMF (0.3 mL) and DMAP (37 mg, 0.303mmol) and stirred overnight at RT. The mixture was dissolved in EtOAcand, after usual aqueous work-up and chromatographic purification, 110mg (78%) of I-A3-PD5-Me-ester were obtained ¹H-NMR (300 MHz, CDCl₃): δ1.71-1.91 (m, 2H), 2.38-2.42 (m, 2H), 2.44 (s, 3H), 2.84-2.95 (m, 4H),3.66 (s, 3H), 3.67 (s, 3H), 4.31-4.34 (m, 4H), 4.43-4.52 (m, 1H),7.31-7.41 (m, 7H), 8.02 (d, 2H, J=9.0 Hz). MS (m/z): 694 [M−H]⁻.

Step 5: Synthesis of prodrug I-A3-PD5: IN Lithium hydroxide (1.2 mL, 1.2mmol) was added to a solution of I-A3-PD5-Me-ester (100 mg, 0.144 mmol)in THF (0.4 mL) at 0° C. and the mixture allowed to attain ambienttemperature. After 30 min, the mixture was concentrated and the residuediluted with water. Acidification with 1N HCl, followed by extractionwith EtOAc, usual aqueous work-up and chromatographic purification gave26 mg (26%) of I-A3-PD5. ¹H-NMR (300 MHz, CD₃OD): δ 1.82-1.97 (m, 1H),2.05-2.13 (m, 1H), 2.30-2.40 (m, 2H), 2.48 (s, 3H), 2.84-2.94 (m, 4H),4.06-4.08 (m, 1H), 4.15-4.22 (m, 4H), 7.30 (d, 2H, J=9 Hz), 7.35-7.41(m, 5H), 7.92 (d, 2H, J=9.0 Hz). MS (m/z): 666 [M−H]⁻.

Example 38

Synthesis of prodrug I-H1-PD1: This prodrug was synthesized as shown inScheme 14, Method B.

Step 1: A solution of metronidazole (5.0 g, 29.22 mmol) and CDI (5.21 g,32.2 mmol) in DCM (100 mL) was stirred overnight at RT. After usualaqueous work-up, 7.32 g of the imidazolide of metronidazole wereobtained, which was used as such in the next step.

Step 2: A solution of the imidazolide of metronidazole (7.32 g) in DMF(30 mL) was added to a solution of SL-1 (6.39 g, 41.43 mmol) in DMF (10mL) and stirred at 60° C. for 2.5 h. The mixture was concentrated andthe residue was taken up in DCM. After usual aqueous work-up andchromatographic purification, 6.32 g (65%) of I-H1-PD1 were obtained.¹H-NMR (300 MHz, CDCl₃): δ 2.15 (bs, 1H), 2.52 (s, 3H), 2.83-2.92 (m,4H), 3.84-3.92 (m, 2H), 4.34 (t, 2H, J=6.0 Hz), 4.51 (t, 2H, J=3.0 Hz),4.53-4.62 (m, 2H), 7.96 (s, 1H).

Example 39

Synthesis of I-H1-PD14: This prodrug was synthesized as described inScheme 14, Method C. Thus, TEA (0.915 mL, 6.56 mmol) and DMAP (cat.)were added to a solution of LI-2C.TFA (541 mg, 3.94 mmol) and theimidazolide of metronidazole (synthesis described in Example 114) (870mg, 3.28 mmol) in DMF (2 mL) and the mixture was heated at 60° C. for3.5 h. The mixture was concentrated and the residue, after usual aqueouswork-up and chromatographic purification, gave 546 mg (48%) ofI-H1-PD14. ¹H-NMR (300 MHz, CDCl₃): δ 2.48 (s, 3H), 2.76-2.96 (m, 4H),3.46 (q, 2H, J=6.0 Hz), 3.87 (t, 2H, J=6.0 Hz), 4.41 (t, 2H, J=6.0 Hz),4.57 (t, 2H, J=4.5 Hz), 7.90 (s, 1H). MS (m/z): 351 [M+H]⁺.

Example 40

Synthesis of prodrug I-H1-PD2: This prodrug was synthesized as describedin Scheme 14, Method C. Thus, CDI (180 mg, 1.1 mmol) was added to asolution of I-H1-PD14 (350 mg, 1.0 mmol) in DMF (2 mL) and stirred at RTfor 4 h. N,N-Dimethylethylenediamine (88 mg, 1.0 mmol) was added andstirred for 3 h. The mixture was concentrated and the residue purifiedby column chromatography to afford 175 mg (38%) of I-H1-PD2. ¹H-NMR (300MHz, CDCl₃): δ 2.28 (s, 3H), 2.49 (s, 6H), 2.51-2.55 (m, 2H), 2.81 (t,2H, J=6.0 Hz), 2.89 (t, 2H, J=6.0 Hz), 3.27-3.33 (m, 2H), 3.46 (q, 2H,J=6.0 Hz), 4.29 (t, 2H, J=6.0 Hz), 4.40 (t, 2H, J=4.5 Hz), 4.57 (t, 2H,J=4.5 Hz), 5.55 (bs, 1H), 7.94 (s, 1H). MS (m/z): 465 [M+H]⁺. Thisproduct was converted to water-soluble hydrochloride salt form using astandard method.

Example 41

Synthesis of prodrug I-H1-PD5: This prodrug was synthesized as describedin Scheme 14, Method A.

Step 1: Synthesis of Intermediate I-S14-PD1: A solution of theimidazolide of LI-1c (1.6 g, 2.98 mmol) in acetonitrile (10 mL) wasadded to a solution of zudovudine (1.0 g, 3.74 mmol) in acetonitrile (20mL) at RT, followed by DMAP (0.914 g, 7.48 mmol) and stirred for 24 h.The mixture was concentrated and the residue, after usual aqueouswork-up and chromatographic purification, gave 1.62 g (79%) ofintermediate I-S14-PD1. ¹H-NMR (300 MHz, CDCl₃): δ 1.95 (s, 3H),2.35-2.45 (m, 2H), 2.78 (t, 2H, J=6.6 Hz), 2.87 (t, 2H, J=6.33 Hz), 3.38(t, 2H, J=6.33 Hz), 4.05 (m, 1H), 4.25 (m, 1H), 4.35-4.41 (m, 4H), 6.20(t, 1H, J=6.16), 7.21-7.33 (m, 9H), 7.42-7.48 (m, 6H) and 8.49 (s, 1H).MS (m/z): 712 [M+Na]⁺.

Step 2: Synthesis of I-H1-PD5: To a solution of I-S14-PD1 in DCM (15 mL)were added triisopropylsilane (0.446 ml, 2.17 mmol), followed by 10% TFAin DCM (15 mL) and stirred at RT for 30 min. The mixture wasconcentrated and purified by column chromatography to afford 0.68 g(70%) of prodrug I-H1-PD5. ¹H-NMR (300 MHz, CDCl₃): δ 1.93 (s, 3H), 2.30(bs, 1H), 2.41-2.48 (m, 2H), 2.88 (t, 2H, J=6.1 Hz), 2.96 (t, 2H, J=6.6Hz), 3.88 (t, 2H, J=5.8 Hz), 4.05 (m, 1H), 4.29 (m, 1H), 4.30-4.48 (m,4H), 6.18 (t, 1H, J=6.3 Hz), 7.34 (s, 1H) and 9.11 (s, 1H). MS (m/z):448 [M+H]⁺, 470 [M+Na]⁺.

Example 42

Synthesis of prodrug I-S22-PD1: This prodrug was synthesized in twosteps as shown in Scheme 22.

Step 1: To a solution of diphosgene (0.35 mL, 2.93 mmol) in DCM (3 mL)was added a solution of LI-1d (0.404 mg, 1.75 mmol), Hunig's base (0.765mL, 4.39 mmol) and the resulting mixture was stirred at RT for 45 min.The mixture was concentrated, the residue dissolved in DCM (5 mL),cooled in an ice-bath and treated with a solution of paclitaxel (500 mg,0.585 mmol), Hunig's base (0.765 mL, 4.39 mmol) and DMAP (cat.) in DCM(5 mL) over 5 min and the resulting mixture was stirred at RT for 2 h.The mixture was purified by column chromatography to give 519 mg (78%)of the protected intermediate S22-I2 as an off-white solid. ¹H NMR (500MHz, CDCl₃): δ 1.14 (s, 3H), 1.28 (s, 3H), 1.68 (s, 3H), 2.04 (s, 3H),2.23 (s, 3H), 2.37-2.45 (m, 2H), 2.46 (s, 3H), 2.50-2.52 (m, 2H),2.90-2.95 (m, 4H), 3.82 (d, 1H, J=7.0 Hz), 4.05 (s, 2H), 4.21 (d, 1H,J=8.5 Hz), 4.32 (d, 1H, J=8.0 Hz), 4.40-4.42 (m, 5H), 4.97 (d, 1H, J=9.5Hz), 5.29 (s, 1H), 5.43 (d, 1H, J=2.5 Hz), 5.69 (d, 1H, J=7.0 Hz), 6.00(dd, 1H, J=9.5 Hz, 2.5 Hz), 6.26-6.29 (m, 2H), 7.02 (d, 1H, J=9.5 Hz),7.38-7.61 (m, 11H), 7.75 (d, 2H, J=7.5 Hz), 8.15 (d, 2H, J=7.5 Hz).

Step 2: To an ice-cold solution of S22-I2 (60 mg, 0.0532 mmol) in MeOH(1 mL) was added 2 drops of methanol saturated with ammonia gas and theresulting mixture was stirred for 1 h. The reaction mixture was purifiedby column chromatography to give 38 mg (69%) of I-S22-PD1 as an offwhite solid. ¹H NMR (500 MHz, CDCl₃): δ 1.14 (s, 3H), 1.23 (s, 3H), 1.68(s, 3H), 1.91 (s, 3H), 2.23 (s, 3H), 2.38-2.42 (m, 2H), 2.46 (s, 3H),2.50-2.58 (m, 2H), 2.84 (t, 2H, J=5.4 Hz), 2.94 (t, 2H, J=6.5 Hz), 3.82(t, 3H, J=6.0 Hz), 4.20 (d, 1H, J=8.5 Hz), 4.31 (d, 1H, J=8.5 Hz),4.35-4.41 (m, 3H), 4.97 (d, 1H, J=7.5 Hz), 5.44 (d, 1H, J=2.5 Hz), 5.69(d, 1H, 7.0 Hz), 6.0 (dd, 1H, J=9.25 Hz, 2.25 Hz), 6.22-6.29 (m, 2H),7.08 (d, 1H, J=9.5 Hz), 7.36-7.60 (m, 11H), 7.78 (d, 2H, J=7.5 Hz), 8.14(d, 2H, J=7.5 Hz).

Example 43

Synthesis of prodrug I-S22-PD2: To a solution of I-S22-PD1 (38 mg,0.0367 mmol) in acetonitrile (0.6 mL) was added succinic anhydride (5mg, 0.044 mmol) and DMAP (cat.). The resulting mixture was stirredovernight at RT and purified by column chromatography to give 12 mg(29%) of prodrug I-S22-PD2 as an off white solid. ¹H NMR (500 MHz,CDCl₃): δ 1.14 (s, 3H), 1.25 (s, 3H), 1.68 (s, 3H), 1.91 (s, 3H), 2.22(s, 3H), 2.36-2.41 (m, 1H), 2.49 (s, 3H), 2.57-2.63 (m, 5H), 2.86-2.89(m, 2H), 2.93 (t, 2H, J=6.5 Hz), 3.79 (d, 1H, J=7.0 Hz), 4.20-4.44 (m,7H), 4.98 (d, 1H, J=8.0 Hz), 5.53 (d, 1H, 3.0 Hz), 5.69 (d, 1H, J=7.0Hz), 6.02 (dd, 1H, J=9.5 Hz, J=3.0 Hz), 6.26-6.29 (m, 2H), 7.20 (d, 1H,J=9.0 Hz), 7.33-7.62 (m, 11H), 7.74 (d, 2H, J=7.5 Hz), 8.14 (d, 2H,J=7.5 Hz). MS (ES⁺) m/z: 1134.44 [M+H]⁺; 1156.56 [M+Na]⁺.

Water solubility: Paclitaxel and its prodrug I-S22-PD2 (2 mg each) weresuspended in 1 mL water or PBS-buffer (pH 7.4). The suspensions weresonicated for 15 min and centrifuged (13,000 g) for 10 min. Thesupernatant was analyzed using HPLC.

HPLC: Waters RP18 column (150×3.9 mM, X-Terra); DAD-HP Agilent (Model1100); eluent: CH₃CN:H₂O (gradient 0-100% acetonitrile in 0-15 min). TheUV-detector was set at 210 nM. The concentrations were determined bymeasuring the relative area of paclitaxel or I-S22-PD2. It was observedthat the solubility of I-S22-PD2 was 20 times more than that ofpaclitaxel. (i.e., ˜0.2 mg/mL).

The following double/mutual prodrugs (Examples 44-80) were synthesizedby the methods depicted in Schemes 17-21, using appropriate therapeuticagents and obvious modifications:

Example 44 Synthesis of Mutual Prodrug of Desloratidine andPseudoephedrine (I-AA-MPD1)

This mutual prodrug was synthesized as depicted in Scheme 21. Thecompound I-AA-MPD1 was obtained as a colorless gum. ¹H-NMR (300 MHz,CDCl₃): δ 1.00 (d, 3H, J=6.9 Hz), 2.27-2.51 (m, 4H), 2.74-2.97 (m, 9H),3.28-3.41 (m, 4H), 3.79 (bs, 2H), 4.28-4.30 (m, 4H), 4.57 (m, 1H),7.04-7.44 (m, 9H), 8.26-8.33 (m, 2H). MS (m/z): 682 [M+H]⁺.

Example 45 Synthesis of Mutual Prodrug of Amlodipine and Lisinopril(I-AA-MPD2)

Step 1: Synthesis of Diethyl Ester of Lisinopril:

To a suspension of lisinopril (10.0 g, 22.62 mmol) in ethanol (150 mL)was added SOCl₂ (4.95 mL, 67.94 mmol) and refluxed for 1.5 h. Anadditional 1 mL of SOCl₂ was added to the mixture every hour for 4 h.The mixture was concentrated and azeotroped with benzene. The resultinghydrochloride was basified with saturated NaHCO₃ and extracted withEtOAc. Usual aqueous work-up gave 12.86 g of lisinopril diethyl ester,which was used without purification. ¹H-NMR (300 MHz, CDCl₃): δ1.23-1.64 (m, 10H), 1.89-2.3 (m, 6H), 2.63-2.66 (m, 2H), 2.80 (bs, 2H),3.19 (t, 2H, J=7.5 Hz), 3.36-3.59 (m, 6H), 4.12-4.19 (m, 4H), 4.4-4.5(m, 1H), 7.14-7.28 (m, 5H). MS [m/z]: 462.4 [M+H]⁺.

Step 2: Synthesis of I-AA-MPD2: CDI (1.23 g, 7.64 mmol) was added to asolution of I-A1-PD2 (Example 18) (3.0 g, 5.09 mmol) in DMF (10 mL) andstirred RT for 3.5 h. A solution of lisinopril diethyl ester (2.34 g,5.09 mmol) in DMF (5 mL) was added and stirred at 65° C. for 8 h. Thereaction was quenched with brine and taken up in EtOAc. After usualaqueous work-up and chromatographic purification, 2.5 g (45%) ofI-AA-MPD2 were obtained. ¹H-NMR (300 MHz, CDCl₃): δ 1.17 (t, 3H, J=7.5Hz), 1.24-1.30 (m, 7H), 1.45-1.80 (m, 7H), 1.90-2.30 (m, 7H), 2.36 (s,3H), 2.70 (bs, 2H), 2.89-2.95 (m, 4H), 3.10-3.20 (bs, 3H), 3.40-3.70 (m,9H), 4.00-4.40 (m, 10H), 4.47-4.53 (m, 1H), 4.68-4.73 (q, 2H, J=13 Hz),5.30 (bs, 1H), 5.39 (s, 1H), 5.65 (bs, 1H), 7.15-7.36 (m, 9H). MS (m/z):1076 [M+H]⁺, 1098 [M+Na]⁺.

Example 46 Synthesis of Mutual Prodrug of Amlodipine and Losartan(I-AA-MPD3a)

This mutual prodrug was synthesized as described in Example 34, withobvious modifications, using the appropriate amino containingtherapeutic agents. The product I-AA-MPD3a was obtained as a cream colorsolid. ¹H-NMR (300 MHz, CDCl₃): δ 0.86 (t, 3H, J=6.6 Hz), 1.16 (t, 3H,J=7.1 Hz), 1.31 (m, 2H), 1.60 (m, 2H), 2.31 (s, 3H), 2.48 (t, 2H, J=7.9Hz), 2.80-2.92 (m, 4H), 3.40 (m, 4H), 3.56 (s, 3H), 4.01 (m, 2H), 4.32(m, 4H), 4.68 (q, 2H, J=6.5 Hz), 5.00 (s, 2H), 5.14 (s, 2H), 5.37 (s,1H), 6.90 (d, 1H, J=7.8 Hz), 7.02-7.22 (m, 5H), 7.33-7.43 (m, 3H),7.50-7.60 (m, 2H). MS (m/z): 1037 [M−H]⁻.

Example 47 Synthesis of Mutual Prodrug of Celecoxib and Valdecoxib(I-AA-MPD4)

This mutual prodrug was synthesized by reacting the imidazolideintermediate of I-A3-PD1 with valdecoxib according to method describedin Scheme 17 with appropriate modifications. This mutual prodrugI-AA-MPD4 was obtained as a white solid. ¹H-NMR (300 MHz, CDCl₃): δ 2.16(s, 3H), 2.29 (s, 3H), 2.71 (bs, 4H), 4.14 (bs, 4H), 6.69 (s, 2H),7.02-7.33 (m, 14H), 7.97 (d, 3H, J=9.0 Hz). MS (m/z): 900 [M−H]⁻.

Example 48 Synthesis of Double Prodrug of Valdecoxib (I-AA-MPD5)

This double prodrug was synthesized by reacting I-A3-PD1 and valdecoxibusing the method B described in Scheme 13. The double prodrug I-AA-MPD5was obtained as an off white solid. ¹H-NMR (300 MHz, CDCl₃): δ 2.40 (s,6H), 2.82 (bs, 4H), 4.20 (bs, 4H), 7.20-7.35 (m, 14H), 7.97 (d, 4H,J=9.0 Hz). MS (m/z): 833 [M−H]⁻.

Example 49 Synthesis of Double Prodrug of Valdecoxib (I-AA-MPD8a)

This mutual prodrug was synthesized using succinic anhydride andvaldecoxib according to method B described in Scheme 13 with appropriatemodifications. This double prodrug I-AA-MPD8a was obtained as anoff-white solid. ¹H-NMR (300 MHz, CDCl₃): δ 2.46 (s, 6H), 2.58 (s, 4H),7.25-7.37 (m, 16H), 7.95 (d, 2H, J=9.0 Hz). MS (m/z): 709 [M−H]⁻.

Example 50 Synthesis of Double Prodrug of Valdecoxib (I-AA-MPD8b)

This mutual prodrug was synthesized using glutaric anhydride andvaldecoxib according to method B described in Scheme 13 with appropriatemodifications. This double prodrug I-AA-MPD8b was obtained as acolorless gum. ¹H-NMR (300 MHz, CDCl₃+CD₃OD): δ 1.68-1.74 (m, 2H), 2.15(t, 4H, J=4.5 Hz), 2.38 (s, 6H), 7.01 (bs, 1H), 7.17-7.30 (m, 14H), 7.50(bs, 1H), 7.88 (d, 4H, J=8.58 Hz). MS (m/z): 723 [M−H]⁻.

Example 51 Synthesis of Mutual Prodrug of Olanzapine and Fluoxetine(I-AA-MPD9)

This mutual prodrug was made according to Scheme 17 with appropriatemodifications. This mutual prodrug I-AA-MPD9 was obtained as a yellowgum. ¹H-NMR (300 MHz, CDCl₃): δ 2.05-2.20 (m, 2H), 2.40 (s, 3H), 2.44(s, 3H), 2.50-2.90 (m, 12H), 3.30-3.80 (m, 4H), 4.10-4.50 (m, 4H), 5.20(bs, 1H), 6.42 (s, 1H), 6.87 (d, 2H, J=8.52 Hz), 7.04-7.36 (m, 9H), 7.42(d, 2H, J=8.67 Hz). MS (m/z): 828 [M+H]⁺.

Example 52 Synthesis of Double Prodrug of Gabapentin (I-AA-MPD10a)

This double prodrug was synthesized as described below:

Step 1: A solution of SL-1 (3.0 g, 19.4 mmol) in DMF (5 mL) was added toa suspension of CDI (9.46 g, 5.83 mmol) in DMF (15 mL) and stirred at RTfor 20 h. The mixture was concentrated and the residue purified bycolumn chromatography. The bis-imidazolide obtained was used as such inthe next step.

Step 2: A solution of the bis-imidazolide (1.0 g, 2.91 mmol) inacetonitrile (3 mL) was added to a dispersion of gabapentin (1.49 g,8.75 mmol) in 1N NaHCO₃ (8 mL) and stirred at RT for 3 d. The mixturewas diluted with water, acidified with 2N HCl and extracted with EtOAc.After usual aqueous work-up and chromatographic purification, 1.04 g(65%) of pure I-AA-MPD10 was obtained. ¹H-NMR (300 MHz, CDCl₃): δ1.20-1.47 (m, 20H), 2.33 (s, 4H), 2.96 (t, 4H, J=5.48 Hz), 3.23 (d, 4H,J=6.5 Hz), 4.31 (t, 4H, J=6.0 Hz), 5.55 (t, 2H, J=6.6 Hz). ESI− MS(m/z): 547 [M−H]⁻.

Example 53 Synthesis of Double Prodrug of Gabapentin Ethyl Ester(I-AA-MPD10b)

A mixture of I-A1-PD8 (2.0 g, 5.26 mmol) and Hunig's base (2.75 mL, 15.8mmol) in DCM (8 mL) was added to a solution of diphosgene (1.27 mL,10.53 mmol) in DCM (4 mL) at 0° C. and stirred for 30 min. The mixturewas concentrated, dissolved in DCM (10 mL) and treated with a solutionof gabapentin ethyl ester hydrochloride (1.86 g, 7.88 mmol) and Hunig'sbase (2.74 mL, 15.77 mmol) in DCM (10 mL). The mixture was stirred for 3h. After usual aqueous work-up, the crude material was purified bypreparative HPLC to afford 2.2 g (69%) of I-AA-MPD10b as a colorlessoil. ¹H-NMR (300 MHz, CDCl₃): δ 1.25 (t, 6H, J=6.0 Hz), 1.35-1.67 (m,20H), 2.33 (s, 4H), 2.91 (t, 4H, J=6.0 Hz), 3.18 (d, 4H, J=6.0 Hz), 4.12(q, 4H, J=6.0 Hz), 4.29 (t, 4H, J=6.0 Hz) 5.42 (bs, 2H). MS: ES+ m/z 605[M+H]⁺, 627 [M+Na]⁺.

Example 54 Synthesis of Mutual Prodrug of Lamotrigine and Gabapentin(I-AA-MPD11)

To a solution of I-A1-PD4 (4.5 g, 10.32 mmol) in acetonitrile (40 mL) atRT was added CDI (2.0 g, 12.38 mmol) and stirred for 3 h. To this wasadded a solution of gabapentin (2.12 g, 12.38 mmol) in 10 ml of 1%NaHCO₃ solution and the mixture was stirred at RT for 24 h. After usualaqueous work-up and chromatographic purification, 2.6 g (40%) ofI-AA-MPD11 was obtained as an off white solid. ¹H NMR (CD₃OD, 300 MHz):δ 1.14-1.48 (m, 10H), 2.28 (s, 2H), 2.99 (t, 2H, J=6.0 Hz), 3.06 (t, 2H,J=6.3 Hz), 3.22 (s, 2H), 4.31 (t, 2H, J=6.0 Hz), 4.46 (t, 2H, J=6.3 Hz),7.39-7.49 (m, 2H), 7.69-7.71 (m, 1H). MS: (ES+) m/z 633.1 (M+H)⁺, 655.1(M+Na)⁺.

Example 55 Synthesis of Mutual Prodrug of Gabapentin Ethyl Ester andLamotrigine (I-AA-MPD12)

To a suspension of lamotrigine (2.70 g, 10.55 mmol) and DMAP (1.28 g,10.55 mmol) in toluene (40 mL) at 110° C. was added a solution of theimidazolide of I-A1-PD4 (4.99 g, 10.55 mmol) THF (20 mL) and stirredovernight at 110° C. The reaction mixture was purified by columnchromatography to afford 0.85 g (12%) of I-AA-MPD12 as a white solid. ¹HNMR (CDCl₃, 300 MHz) δ 1.24 (t, 2H, J=7.2 Hz), 1.36-1.77 (m, 10H), 2.29(s, 2H), 2.93-3.03 (m, 4H), 3.22 (d, 2H, J=6.6 Hz), 4.11 (q, 2H, J=7.2Hz), 4.34 (t, 2H, J=6.6 Hz), 4.47 (t, 2H, J=6.3 Hz), 5.65 (t, 1H),7.34-7.41 (m, 2H), 7.60-7.63 (m, 1H). MS: ES+ m/z 661 (M+H)⁺, 682(M+Na)⁺.

Example 56 Synthesis of Mutual Prodrug of Gabapentin Ethyl Ester andLevetiracetam (I-AA-MPD13)

To a solution of levetiracetam (1.0 g, 5.87 mmol) in DCE (25 mL) and DCM(5 mL) at RT was added oxalyl chloride (895 mg, 7.05 mmol). The reactionmixture was refluxed for 8 h, after which it was cooled to RT and asolution of I-A1-PD8 (2.67 g, 7.05 mmol) in DCE (20 mL) was addeddrop-wise. The resulting mixture was stirred at RT for 18 h. After usualaqueous work-up and chromatographic purification, 1.63 g (48%) ofI-AA-MPD13 was obtained as a yellow oil. ¹H NMR (CDCl₃, 300 MHz): δ 0.87(t, 3H, J=7.4 Hz), 1.25 (t, 3H, J=7.1 Hz), 1.34-1.52 (m, 10H), 1.82-2.01(m, 4H), 2.28 (s, 2H), 2.40 (t, 2H, J=7.0 Hz), 2.89-2.94 (m, 4H),3.04-3.11 (m, 1H), 3.19 (d, 2H, J=6.6 Hz), 3.66-3.75 (m, 1H), 4.07-4.16(m, 3H), 4.27-4.35 (m, 4H), 5.48 (t, 1H, J=6.5 Hz), 8.18 (bs, 1H). MS:(ES⁺): m/z 576.1 [M+H]⁺; 598.1 [M+Na]⁺. (ES⁻): m/z 574.2 [M−H]⁻.

Example 57 Synthesis of Mutual Prodrug of Gabapentin Ethyl Ester andValproic Acid (I-AA-MPD14)

This mutual prodrug was synthesized according method outlined in Scheme18. This mutual prodrug I-AA-MPD14 was obtained as oil. MS (m/z): 592[M+H]⁺.

Example 58 Synthesis of Mutual Prodrug of Gabapentin Ethyl Ester andValproic Acid (I-AA-MPD15)

This mutual prodrug was synthesized according to the method outlined inScheme 18. The mutual prodrug I-AA-MPD15 was obtained as a yellow oil.MS (m/z): 620 [M+H]⁺.

Example 59 Synthesis of Mutual Prodrug of Gabapentin Ethyl Ester andValproic Acid (I-AA-MPD16)

To a suspension of valpromide (750 mg, 5.24 mmol) in DCE (15 mL) at 0-5°C. was added oxalyl chloride (0.5 mL, 6.29 mmol) and refluxed overnight.The reaction mixture was cooled to RT, treated with a solution ofI-A1-PD8 (2.18 g, 5.76 mmol) in DCE (2 mL) and stirred at RT for 2 h.The reaction mixture was purified by column chromatography to afford1.61 g (51%) of I-AA-MPD16 as a colorless oil. ¹H NMR (CDCl₃, 300 MHz):δ 0.89 (t, 6H, J=7.09 Hz), 1.25 (t, 3H, J=6.96 Hz), 1.31-1.69 (m, 18H),2.29 (s, 3H), 2.89-2.99 (m, 4H), 3.20 (d, 2H, J=6.47 Hz), 4.13 (q, 2H),4.33 (t, 2H, J=6.71 Hz), 4.40 (t, 2H, J=5.97 Hz), 5.54 (t, 1H), 8.29 (brs, 1H). MS: ES+ m/z 549 [M+H]⁺, 571 [M+Na]⁺.

Example 60 Synthesis of Double Prodrug of Valproic Acid (I-AA-MPD22)

To a suspension of valpromide (3.0 g, 20.95 mmol) in DCE (30 mL) at 0-5°C. was added oxalyl chloride (1.3 mL, 15.08 mmol) and refluxedovernight. The reaction mixture was cooled to RT, a solution of SL-1(0.808 g, 5.24 mmol) in DCE (3 mL) was added and stirred overnight.After usual work-up and chromatographic purification, 1.97 g (43%) ofI-AA-MPD22 were obtained as a white solid. ¹H NMR (CDCl₃, 300 MHz): δ0.89 (t, 12H, J=7.18 Hz), 1.28-1.66 (m, 16H), 2.94-2.95 (m, 2H), 3.02(t, 6H, J=6.51 Hz), 4.42 (t, 4H, J=6.47 Hz). MS: m/z 493.2 [M+H]⁺, 510.0[M+NH₄]⁺, 515.10 [M+Na]⁺.

Example 61 Synthesis of Mutual Prodrug of Gabapentin Ethyl Ester andValproic Acid (I-AA-MPD27)

Step 1: To a solution of I-A1-PD8 (4.0 g, 10.54 mmol) in THF (25 mL) wasadded CDI (2.22 g, 13.7 mmol) and stirred at RT for 90 min. To this wasadded t-butyl carbazate (1.39 g, 10.54 mmol) and DMAP (1.288 g, 10.54mmol), and stirred overnight at RT. After usual aqueous work-up andchromatographic purification, 4.0 g (91%) of the intermediateboc-hydrazide was obtained as a colorless gummy material. ¹H NMR (CDCl₃,300 MHz): δ 1.25 (t, 3H, J=7.1 Hz), 1.43 (s, 9H), 1.31-1.74 (m, 10H),2.30 (s, 2H), 2.90-3.01 (m, 4H), 3.20 (d, 2H, J=6.6 Hz), 4.17 (q, 2H,J=7.1 Hz), 4.32 (t, 2H, J=6.5 Hz), 4.39 (t, 2H, J=6.5 Hz), 5.42 (br s,1H), 6.04 (br s, 1H), 6.98 (br s, 1H).

Step 2: To a solution of the above boc-hydrazide (4.0 g, 7.44 mmol) inDCM (20 mL) was added 50% TFA/DCM (10 mL) and stirred at RT for 1 h. DCMwas removed under vacuum, the resulting residue triturated with diethylether (2×20 mL) and dried to give a colorless oil, which was dissolvedin THF (20 mL). To the above solution at 0-5° C. was added TEA (2.1 mL,14.88 mmol), valproic acid (1.18 g, 8.184 mmol), DCC (2.3 g, 11.16 mmol)and DMAP (0.909 g, 7.44 mmol) and the mixture was stirred overnight atRT. The mixture was filtered, concentrated and purified by columnchromatography to afford 2.59 g (51%) of I-AA-MPD27 as a colorless gummymaterial. ¹H NMR (CDCl₃, 300 MHz): δ 0.85 (t, 6H, J=7.2 Hz), 1.3 (t, 6H,J=7.11 Hz), 1.21-1.80 (m, 26H), 2.2-2.3 (m, 1H), 2.35 (s, 2H), 2.81-2.94(m, 4H), 3.21 (d, 2H, J=6.6 Hz), 3.65-3.68 (m, 1H), 4.19 (q, 2H, J=7.11Hz), 4.36 (t, 2H, J=6.51 Hz), 4.39 (t, 2H, J=6.51 Hz), 5.51 (t, 1H),8.17 (s, 1H). MS: m/z 712 [M+Na]⁺, 728 [M+K]⁺, 688 [M−H]⁻.

Example 62 Synthesis of Mutual Prodrug of Valproic Acid and NicotinicAcid (I-CC-MPD.1)

Step 1: To a solution of nicotinyl chloride hydrochloride (3.16 g, 17.76mmol) and LI-2c (3 g, 11.84 mmol) in THF (50 mL) was added TEA (8.3 mL,59.2 mmol) and stirred overnight at RT. After usual aqueous work-up andchromatographic purification, 4.14 g (97%) of LI-2c-nicotinate ester wasobtained as a colorless oil. ¹H NMR (CDCl₃, 300 MHz): δ 1.43 (s, 9H),2.82 (t, 2H, J=6.31 Hz), 3.42-3.48 (q, 2H), 4.62 (t, 2H, J=6.59 Hz),7.29-7.33 (m, 1H), 8.30 (d, 1H, J=7.95 Hz), 8.78 (dd, 1H, J=4.86, 1.72Hz), 9.23 (d, 1H, J=2.13 Hz). MS: m/z 358 [M+H]⁺, 381 [M+Na]⁺, 739[2M+Na]⁺.

Step 2: To a solution of LI-2c-nicotinate ester (0.92 g, 2.50 mmol) inDCM (5 mL) was added 50% TFA/DCM (5 mL) and stirred for 1 h. Reactionmixture was concentrated and the residual TFA salt was used as such inStep 3.

Step 3: To a solution of valproic acid (0.37 g, 2.56 mmol) in THF (5 mL)was added CDI (0.5 g, 3.08 mmol) and stirred for 2 h. This was treatedwith a solution of the above TFA salt, TEA (0.7 mL, 5.13 mmol) and DMAP(50 mg, 0.41 mmol) in THF (10 mL) and the mixture was stirred overnightat RT. After usual aqueous work-up and chromatographic purification, 0.7g (71%) of I-CC-MPD1 was obtained as a white solid. ¹H NMR (CDCl₃, 500MHz): δ 0.88 (t, 6H, J=7 Hz), 1.25-1.59 (m, 8H), 2.06-2.08 (m, 1H), 2.86(t, 2H, J=6 Hz), 3.05 (t, 2H, J=7 Hz), 3.58-3.61 (q, 2H, J=9.0 Hz), 4.63(t, 2H, J=6.5 Hz), 7.40-7.42 (m, 1H), 8.30 (dt, 1H, J=8.0, 2.0 Hz), 8.79(dd, 1H, J=5.0, 2.0 Hz), 9.23 (d, 1H, J=0.5 Hz). MS: m/z 385 [M+H]⁺, 407[M+Na]⁺, 423 [M+K]⁺.

Example 63 Synthesis of Mutual Prodrug of Valproic Acid and NicotinicAcid (I-CC-MPD2)

This mutual prodrug was synthesized as described in Example 62, withobvious modifications. 0.612 g (41%) of I-CC-MPD2 was obtained as awhite solid. ¹H NMR (CDCl₃, 300 MHz): δ 0.89 (t, 6H, J=7.23 Hz),1.24-1.62 (m, 8H), 2.34-2.42 (m, 1H), 2.92 (t, 2H, J=6.83 Hz), 2.98 (t,2H, J=6.04 Hz), 3.78-3.84 (q, 2H), 4.37 (t, 2H, J=6.79 Hz), 7.36-7.41(m, 1H), 8.15 (d, 1H, J=7.92 Hz), 8.73 (d, 1H, J=4.78 Hz), 9.02 (s, 1H).MS: m/z 385 [M+H]⁺, 419 [M+HCl]⁺, 383 [M−H]⁻.

Example 64 Synthesis of Mutual Prodrug of Zidovudine and Lamivudine(I-HH-MPD1)

Step 1: Synthesis of Intermediate I-S17-PD11:

4-Nitrophenyl chloroformate (0.27 g, 1.34 mmol) was added to a solutionof the I-H1-PD5 (0.4 g, 0.89 mmol) and pyridine (76 μL, 1 mmol) in DCM(10 mL) and stirred at RT for 15 h. The mixture was concentrated and theresidue purified by column chromatography to give 0.29 g (53%) ofI-S17-PD11. ¹H-NMR (300 MHz, CDCl₃): δ 1.93 (s, 3H), 2.45 (m, 2H),2.97-3.06 (m, 4H), 4.05 (m, 1H), 4.41 (m, 1H), 4.40-4.49 (m, 4H), 4.54(t, 2H, J=6.5 Hz), 6.17 (t, 1H, J=6.0 Hz), 7.33 (s, 1H), 7.39 (d, 2H,J=4.8 Hz), 8.28 (d, 2H, J=4.8 Hz) and 8.50 (s, 1H). MS (m/z): 635[M+Na]⁺.

Step 2: Synthesis of I-HH-MPD1: Lamivudine (45 mg, 0.196 mmol) and DMAP(48 mg, 0.39 mmol) were added to a solution of I-S17-PD11 (80 mg, 0.13mmol) in DMF (1.5 mL) and stirred at RT for 30 min. The mixture wasconcentrated and purified by column chromatography to give 40 mg (43%)of product I-HH-MPD1. ¹H-NMR (300 MHz, CDCl₃): δ 1.90 (s, 3H), 2.45 (t,2H, J=6.1 Hz), 3.05 (t, 4H, J=6.2 Hz), 3.20 (m, 1H), 3.53 (m, 1H), 4.08(m, 1H), 4.30-4.80 (m, 8H), 5.45 (t, 1H, J=3.0 Hz), 5.90 (d, 1H, J=7.5Hz), 6.17 (t, 1H), 6.30 (t, 1H), 7.55 (s, 1H) and 7.90 (d, 1H, J=7.50Hz). MS (m/z): 725 [M+Na]⁺.

Example 65 Synthesis of Mutual Prodrug of Zidovudine and Lamivudine(I-HH-MPD2b)

This mutual prodrug was synthesized according to the method outlined inScheme 18. The mutual prodrug I-HH-MPD2b was obtained as a white solid.¹H-NMR (300 MHz, CDCl₃): δ 1.97 (s, 3H), 2.42 (m, 2H), 2.90-2.94 (m,16H), 3.06 (m, 1H), 3.40-3.44 (m, 8H), 3.50-3.56 (m, 1H), 3.71-3.73 (m,1H), 4.95 (m, 1H), 4.27-4.30 (m, 4H), 4.37-4.49 (m, 4 h), 5.32 (t, 1H,J=5.1 Hz), 5.83 (d, 1H, J=6.6 Hz), 6.07 (m, 1H), 6.33 (bs, 1H),7.20-7.25 (m, 1H), 7.74 (m, 1H). MS (m/z): 954 [M+Na]⁺.

Example 66 Synthesis of Mutual Prodrug of Cetirizine and Pseudoephedrine(I-CA-MPD1)

Step 1: Synthesis of Intermediate I-S17-PD11:

This intermediate was prepared by reacting I-C1-PD10 with p-nitrophenylchloroformate by a procedure similar to that described in Example 64.The desired intermediate I-S17-PD11 was obtained as a gum. ¹H-NMR (300MHz, CDCl₃): δ 2.49-2.71 (m, 10H), 2.95 (t, 2H, J=6.6 Hz), 3.01 (t, 2H,J=6.5 Hz), 3.73 (bs, 2H), 4.13 (s, 2H), 4.22 (s, 1H), 4.41 (t, 2H, J=6.6Hz), 4.53 (t, 2H, J=6.6 Hz), 7.18-7.40 (m, 11H), 8.28 (d, 2H, J=7.1 Hz).

Step 2: The mutual prodrug I-CA-MPD1 was synthesized by reactingintermediate I-S17-PD11 with pseudoephidrine by a procedure similar tothat described in Example 64, Step 2. The desired mutual prodrugI-CA-MPD1 was obtained as a colorless gummy material. ¹H-NMR (300 MHz,CDCl₃): δ 0.99-1.09 (d, 3H, J=6.6 Hz), 2.45 (bs, 4H), 2.68 (bs, 6H),2.90 (s, 3H), 2.91-2.94 (m, 4H), 3.71 (bs, 3H), 4.11 (s, 2H), 4.18 (s,1H), 4.26-4.41 (m, 4H), 4.56 (m, 2H), 7.17-7.35 (m, 12H). MS (m/z): 716[M+H]⁺.

Example 67 Synthesis of Mutual Prodrug of Gabapentin Ethyl Ester andNaproxen (I-CA-MPD5)

This mutual prodrug was synthesized by reacting I-A1-PD8 and Naproxenusing Scheme 11, Method B. This mutual prodrug was obtained as colorlessoil. ¹H-NMR (300 MHz, CDCl₃): δ 1.25 (t, 3H, J=7.1 Hz), 1.30-1.55 (m,10H), 1.57 (d, 3H, J=7.1 Hz), 2.27 (s, 2H), 2.84 (q, 4H, J=6.4 Hz), 3.18(d, 2H, J=6.7 Hz), 3.80-3.88 (m, 1H), 3.91 (s, 3H), 4.12 (q, 2H, J=7.1Hz), 4.20-4.40 (m, 4H), 5.35 (bt, 1H), 7.05-7.20 (m, 2H), 7.39 (dd, 1H,J=1.8 Hz, 8.4 Hz), 7.60-7.73 (m, 3H). MS (m/z): 592 [M+H]⁺, 614 [M+Na]⁺.

Example 68 Synthesis of Mutual Prodrug of Valproic Acid and NicotinicAcid (I-CA-MPD14)

This mutual prodrug was synthesized using valpromide and nicotinylchloride hydrochloride, according to the methods described in Scheme 13and Scheme 17, with obvious modifications. 1.0 g of the mutual prodrugI-CA-MPD14 was obtained as a yellow oil. ¹H NMR (CD₃OD, 300 MHz): δ 0.87(t, 6H, J=6 Hz), 1.26-1.75 (m, 9H), 2.83 (s, 1H), 2.95-3.0 (m, 4H), 3.81(t, 2H, J=6 Hz), 4.44 (t, 2H, J=6 Hz), 7.0 (s, 1H), 7.4 (bs, 1H), 7.42(m, 1H), 8.20 (d, 1H), 8.65-8.74 (bs, 2H), 9.0 (s, 1H). MS: ES⁺ m/z428.1 [M+H]⁺, 450.1 [M+Na]⁺.

Example 69 Synthesis of Mutual Prodrug of Valproic Acid and NicotinicAcid (I-CA-MPD15)

To a solution of I-C1-PD13 (1.5 g, 4.63 mmol) and nicotinyl chloridehydrochloride (0.99 g, 5.56 mmol) in THF (25 mL) was added TEA (2 mL,13.89 mmol) at 0° C. and stirred for 20 h at RT. After usual aqueouswork-up and chromatographic purification, 1.0 g (83%) of I-CA-MPD15 wasobtained as a yellow viscous liquid. ¹H NMR (CD₃OD, 500 MHz): δ 0.89 (t,6H, J=5.0 Hz), 1.29-1.33 (m, 8H), 1.64 (bs, 2H), 3 (t, 2H, J=5.0 Hz),3.07 (t, 2H, J=5.0 Hz), 4.42 (t, 2H, J=5.0 Hz), 4.63 (t, 2H, J=5.0 Hz),7.41-7.43 (m, 1H), 8.31 (bs, 1H), 8.78 (bs, 1H), 9.26 (s, 1H). MS: ES⁺m/z 429 [M+H]⁺, 451 [M+Na]⁺, 467 [M+K]⁺.

Example 70 Synthesis of Mutual Prodrug of Gabapentin Ethyl Ester andNicotinic Acid (I-CA-MPD18)

To a solution of BOC deprotected I-S12-PD2 (synthesized as described inScheme 12, Method C, and then deprotected using a known general BOCdeprotection method) (3.76 g, 7.64 mmol) in THF (30 mL) was addednicotinyl chloride hydrochloride (1.5 g, 8.40 mmol), followed by TEA(4.26 mL, 30.56 mmol) and stirred overnight at RT. After usual aqueouswork-up and chromatographic purification, 0.87 g (23%) of I-CA-MPD18 wasobtained as a yellow oil. ¹H NMR (CDCl₃, 300 MHz): δ 1.24 (t, 3H, J=6.0Hz), 1.27-1.47 (m, 10H), 2.27 (s, 2H), 2.90-3.17 (m, 4H), 3.16 (d, 2H,J=6.0 Hz), 3.79 (q, 2H, J=6.0 Hz), 4.10 (q, 2H, J=6.0 Hz), 4.36 (t, 2H,J=6.0 Hz), 5.56 (bt, 1H, J=6.0 Hz), 7.32-7.38 (m, 1H), 8.17 (d, 1H,J=9.0 Hz), 8.71 (d, 1H, J=6.0 Hz), 9.07 (s, 1H). MS: (ES)⁺ m/z 484(M+H)⁺, 506 (M+Na)⁺; (ES)⁻ m/z 482 (M−H)⁺.

Example 71 Synthesis of Mutual Prodrug of Levetiracetam and ValproicAcid (I-CA-MPD19)

To a solution of levetiracetam (1.0 g, 5.87 mmol) in DCE (20 mL) and DCM(4 mL) was added oxalyl chloride (894 mg, 7.05 mmol) and heated at 80°C. for 7 h. The reaction mixture was cooled to RT, a solution ofI-C1-PD11 (1.97 g, 7.05 mmol) in DCE (10 mL) was added and stirred at RTfor 18 h. After usual aqueous work-up and chromatographic purification,1.73 g (61%) of I-CA-MPD19 was obtained as a yellow oil. ¹H NMR (CDCl₃,300 MHz): δ 0.85-0.91 (m, 9H), 1.24-1.62 (m, 8H), 1.80-2.05 (m, 4H),2.34-2.44 (m, 3H), 2.91 (t, 4H, J=6.0 Hz), 3.03-3.12 (m, 1H), 4.06-4.09(m, 1H), 4.31-4.36 (m, 4H), 8.32 (bs, 1H). MS: (ES⁺) m/z 477.1 [M+H]⁺,498.9 [M+Na]⁺ (ES)⁻ m/z 475.0 [M−H]⁻.

Example 72 Synthesis of Mutual Prodrug of Gabapentin Ethyl Ester andValproic Acid (I-CA-MPD21)

This mutual prodrug was synthesized by following a route depicted inScheme 19, with obvious modifications. The mutual prodrug I-CA-MPD21 wasobtained as a colorless oil. ¹H-NMR (CDCl₃, 300 MHz): δ 0.81 (t, 6H,J=7.19 Hz), 1.15-1.60 (m, 21H), 2.20 (s, 2H), 2.25-2.35 (m, 1H), 2.84(t, 4H, J=6.6 Hz), 3.11 (d, 2H, J=6.7 Hz), 4.05 (q, 2H, J=7.16 Hz and17.3 Hz), 4.15-4.25 (m, 4H), 5.43 (bt, 1H). MS (m/z): 506 [M+H]⁺, 528[M+Na]⁺.

Example 73 Synthesis of Mutual Prodrug of Gabapentin Ethyl Ester andNicotinic Acid (I-CA-MPD22)

To a suspension of nicotinyl chloride hydrochloride (0.35 g, 1.97 mmol)in THF (3 mL) at 0° C. was added TEA (0.82 mL, 5.91 mmol). After 5 min,a solution of I-A1-PD8 (0.5 g, 1.31 mmol) and TEA (0.27 mL, 1.97 mmol)in THF (4 mL) was added and stirred overnight at RT. The mixture waspurified by column chromatography to afford 0.573 g (90%) of I-CA-MPD22as a yellow oil. ¹H NMR (CDCl₃, 300 MHz): δ 1.24 (t, 3H, J=6.0 Hz),1.27-1.47 (m, 10H), 2.27 (s, 2H), 2.94 (t, 2H, J=6.0 Hz), 3.07 (t, 2H,J=6.0 Hz), 3.19 (d, 2H, J=6.0 Hz), 4.12 (q, 2H, J=6.0 Hz), 4.32 (t, 2H,J=6.0 Hz), 4.62 (t, 2H, J=6.0 Hz), 5.29 (bs, 1H), 7.36-7.42 (m, 1H),8.30 (t, 1H, J=3.0 Hz), 8.78 (dd, 1H, J=1.69 Hz), 9.24 (s, 1H). MS:(ES)⁺ m/z 485 (M+H)⁺, 507 (M+Na)⁺.

Example 74 Synthesis of Mutual Prodrug of Lamotrigine and Valproic Acid(I-CA-MPD23)

To a suspension of lamotrigine (0.455 g, 1.78 mmol) and DMAP (0.217 g,1.78 mmol) in toluene (10 mL) at 110° C. was added a solution of theimidazolide of I-C1-PD11 (0.665 g, 1.78 mmol) in THF (5 mL). Thereaction was stirred at 110° C. overnight and purified by columnchromatography to afford 0.20 g (20%) of I-CA-MPD23 as a white solid. ¹HNMR (300 MHz, CDCl₃): δ 0.86-0.90 (m, 6H), 1.20-1.44 (m, 6H), 1.53-1.62(m, 2H), 2.36-2.39 (m, 1H), 2.90-3.0 (m, 4H), 4.34 (t, 2H, J=6.3 Hz),4.46 (t, 2H J=6.6 Hz), 7.36-7.38 (m, 2H), 7.60-7.63 (m, 1H). MS: (ES+)m/z 562 (M+H)⁺, 585 (M+Na)⁺.

Example 75 Synthesis of Mutual Prodrug of Lamotrigine and Nicotinic Acid(I-CA-MPD24)

A solution of I-A1-PD4 (0.5 g, 1.14 mmol) and TEA (0.5 mL, 2.87 mmol) inTHF (5 mL) was added to a suspension of nicotinyl chloride (0.305 g,1.71 mmol) and 0.5 mL TEA in THF (5 mL). The mixture was stirred at RTfor 24 h. After usual aqueous work-up and chromatographic purification,0.15 g (14%) of I-CA-MPD24 were obtained as a white solid. ¹H NMR(CDCl₃, 500 MHz): δ 3.06 (t, 2H, J=6.5 Hz), 3.10 (t, 2H, J=6.5 Hz), 4.49(t, 2H, J=6.5 Hz), 4.65 (t, 2H, J=6.5 Hz), 7.38-7.43 (m, 3H), 7.60-7.62(m, 1H), 8.33-8.36 (m, 1H), 8.81 (m, 1H), 9.35 (bs, 1H). MS: (ES+) m/z540.9 (M+H)⁺.

Example 76 Synthesis of Mutual Prodrug of Lamotrigine and Nicotinic Acid(I-CA-MPD25)

This mutual prodrug was synthesized using lamotrigine and nicotinylchloride hydrochloride, according to the methods outlined in Scheme 12and Scheme 17. 0.8 g (44%) of I-CA-MPD25.HCl were obtained as an offwhite solid. ¹H NMR (D₂O, 500 MHz): δ 2.93 (t, 2H, J=6.5 Hz), 3.10 (t,2H, J=6.0 Hz), 3.69 (t, 2H, J=6.5 Hz), 4.49 (m, 2H), 7.37-7.43 (m, 3H),7.69-7.71 (m, 1H), 8.05-8.07 (m, 1H), 8.78-8.79 (m, 1H), 9.30 (bs, 1H).MS: (ES+) m/z 539.9 (M+H)⁺, 561.8 (M+Na)⁺.

Example 77 Synthesis of Mutual Prodrug of Metronidazole and Norfloxacin(I-AH-MPD1)

Step 1: Synthesis of Imidazolide of I-H1-PD1:

CDI (319 mg, 1.97 mmol) was added to a solution of I-H1-PD1 (577 mg,1.64 mmol) in DMF (8 mL) and stirred at RT for 4 h. The mixture wasconcentrated and the residue purified by column chromatography to give395 mg (54%) of the imidazolide of I-H1-PD1. ¹H-NMR (300 MHz, CDCl₃): δ2.50 (s, 3H), 2.92 (t, 2H, J=6.0 Hz), 3.00-3.10 (m, 2H), 4.36 (t, 2H,J=3.0 Hz), 4.47-4.51 (m, 2H), 4.57-4.70 (m, 4H), 7.07 (s, 1H), 7.43 (s,1H), 7.95 (s, 1H), 8.15 (s, 1H). MS (m/z): 446 [M+H]⁺.

Step 2: Synthesis of I-AH-MPD1: A solution of the imidazolide ofI-H1-PD1 (100 mg, 0.224 mmol) in DMF (1 mL) was added to a suspension ofnorfloxacin (86 mg, 0.269 mmol) in DMF (2 mL) and stirred at RT for 60h. The mixture was concentrated and the residue purified by columnchromatography to give 35 mg (22%) of I-AH-MPD1. ¹H-NMR (300 MHz,CDCl₃): δ 1.59 (t, 3H, J=7.5 Hz), 2.53 (s, 3H), 2.86-2.97 (m, 4H),3.27-3.30 (m, 4H), 3.72 (t, 4H, J=4.5 Hz), 4.32-4.40 (m, 6H), 4.48-4.52(m, 2H), 4.59-4.63 (m, 2H), 6.85 (d, 1H, J=6.0 Hz), 7.96 (s, 1H), 8.09(d, 1H, J=12.0 Hz), 8.68 (s, 1H). MS (m/z): 697 [M+H]⁺.

The following mutual prodrugs (Examples 78-80) were obtained accordingto procedures similar to those described in Example 77, with thesubstitution of the appropriate pairs of amino-containing andhydroxyl-containing therapeutic agents:

Example 78 Synthesis of Mutual Prodrug of Metronidazole and Norfloxacin(I-AH-MPD3b)

The mutual prodrug I-AH-MPD3b was obtained as a yellow solid. ¹H-NMR(300 MHz, CDCl₃): δ 1.59 (t, 3H, J=7.1 Hz), 2.49 (s, 3H), 2.82-2.98 (m,10H), 3.30 (t, 4H, J=4.5 Hz), 3.39 (bs, 4H), 3.72 (t, 4H, J=4.8 Hz),4.38 (dt, 8H, J=26.2, 6.4 Hz), 4.61 (t, 2H, J=4.8 Hz), 6.86 (d, 1H,J=6.4 Hz), 7.95 (s, 1H), 8.07 (bd, 1H, J=12.8 Hz), 8.67 (s, 1H), 14.9(s, 1H). MS (m/z): 811.26 [M+H]⁺.

Example 79 Synthesis of Mutual Prodrug of Gabapentin and Tramadol(I-AH-MPD7)

The mutual prodrug was synthesized according to the method in Scheme 15with obvious modifications. The mutual prodrug I-AH-MPD7 was obtained asa colorless gummy material. ¹H-NMR (300 MHz, CDCl₃): δ 1.25 (t, 3H,J=7.1 Hz), 1.32-2.45 (m, 30H), 2.91-2.99 (m, 4H), 3.16 (t, 2H, J=7.3Hz), 3.80 (s, 3H), 4.08-4.15 (q, 2H, J=7.1 Hz), 4.28-4.40 (m, 4H), 5.4(t, 1H), 6.74-6.81 (m, 3H), 7.23-7.29 (t, 1H, J=8 Hz). MS (m/z): 669.30[M+H]⁺.

Example 80 Synthesis of Mutual Prodrug of Venlafaxine and Paroxetine(I-AH-MPD8)

The mutual prodrug was synthesized according to the method outlined inScheme 15 with obvious modifications. The mutual prodrug I-AH-MPD8 wasobtained as a white sticky solid. ¹H-NMR was consistent with theexpected structure. MS: m/z 812 [M]⁺.

Example 81 Synthesis of NO-Releasing Prodrug of Valproic Acid(I-C1-NOPD1)

This prodrug was synthesized as shown in Scheme 11, Method B using asreagents valproic acid (725 mg, 5.03 mmol), LI-2b (1 g, 5.03 mmol), TEA(611 mg, 6.04 mmol), DCC (1.25 g, 6.04 mmol) and DMAP (100 mg). Yield:832 mg (51%). ¹H-NMR (300 MHz, CDCl₃): δ 0.89 (t, 6H, J=7.09 Hz),1.22-1.77 (m, 8H), 2.36-2.40 (m, 1H), 2.93-3.00 (m, 4H), 4.34 (t, 2H,J=6.8 Hz), 4.70 (t, 2H, J=6.35 Hz). MS (CI)⁺ m/z: 326 [M+H]⁺.

Example 82 Synthesis of NO-Releasing Prodrug of Valproic Acid(I-C1-NOPD3a)

This prodrug was prepared as shown in Scheme 13, Method A. Thus, to astirred mixture of valproyl isocyanate, which was freshly prepared fromvalpromide (0.7 g, 4.90 mmol [valpromide was synthesized from valproicacid by using known methods as shown in Scheme 11, Method I) using aknown method (see J. Org. Chem., 1962, 27, 3742) in DCM (20 mL) at RTwas added a solution of LI-2b (0.976 g, 4.90 mmol) in DCM (5 mL)drop-wise and stirred at RT for 2 h. The mixture was concentrated andthe residue, after usual aqueous work-up and chromatographicpurification, afforded 0.6 g (33%) of prodrug I-C1-NOPD3a. ¹H-NMR datais consistent with the expected structure. MS: [ES]⁺ m/z 391 [M+Na]⁺,407.2 [M+K]⁺; [EI]⁺ m/z 368 [M+H]⁺.

Example 83 Synthesis of NO-Releasing Prodrug of Aspirin (I-C1-NOPD4)

This prodrug was synthesized as shown in Scheme 11, Method D. Thus, to asolution of aspirin (3.0 g, 16.65 mmol) in THF (30 mL) at 0° C. wasadded oxalyl chloride (1.86 mL, 21.64 mmol) and heated at 70° C. for 2h. The mixture was concentrated, the residue was dissolved in THF (30mL) and treated with a solution of LI-2a (3.61 g, 16.65 mmol), TEA (3.48mL, 24.97 mmol) and DMAP (361 mg) in THF (20 mL). The resulting mixturewas stirred at RT for 2 h and filtered through celite. The filtrate wasconcentrated and the residue purified by column chromatography to afford3.06 g (48%) of the bromide S11-I1. ¹H-NMR (300 MHz, CDCl₃): δ 2.35 (s,3H), 3.01-3.12 (m, 4H), 3.61 (t, 2H, J=6.5 Hz), 4.53 (t, 2H, J=6.0 Hz),7.11 (dd, 1H, J=8 Hz, 1 Hz), 7.32 (t, 1H, J=7.6 Hz), 7.57 (t, 1H, J=7.6Hz), 8.03 (dd, 1H, J=7.8 Hz, 1.6 Hz). MS (ES⁺) m/z: 403.92 (M+Na)⁺.

To a solution of S11-I1 (2.0 g, 5.27 mmol) in acetonitrile (20 mL) at 0°C. was added AgNO₃ (1.07 g, 6.32 mmol) in the dark. The mixture wasstirred at RT for 1.5 h, filtered through celite and concentrated. Theresidue, after usual aqueous work-up and chromatographic purification,afforded 0.965 g (50%) pure I-C1-NOPD4. ¹H-NMR (300 MHz, CDCl₃): δ 2.36(s, 3H), 2.98 (t, 2H, J=6.8 Hz), 3.05 (t, 2H, J=6.4 Hz), 4.54 (t, 2H,J=6.4 Hz), 4.70 (t, 2H, J=6.8 Hz), 7.12 (d, 1H, J=8 Hz), 7.33 (t, 1H,J=7.6 Hz), 7.59 (t, 1H, J=7.5 Hz), 8.03 (dd, 1H, J=7.8 Hz, 1 Hz). MS(ES)⁺ m/z: 379.11 (M+NH₄)⁺, 383.98 (M+Na)⁺.

Example 84 Synthesis of NO-Releasing Prodrug of Aspirin (I-C1-NOPD5a)

As shown in Scheme 11, Method H, this prodrug was synthesized in threesteps:

Step 1: To a suspension of aspirin (1 g, 5.55 mmol) in benzene (15 mL)and DMF (1 drop) at 0-5° C. was added a solution of oxalyl chloride (0.6mL, 6.66 mmol) in benzene (5 mL) and stirred at 85° C. for 2 h. Thereaction mixture was concentrated, and the crude acid chloride was usedimmediately in the next step.

Step 2: To a solution of the above acid chloride in benzene (30 mL) wasadded silver cyanate (998 mg, 6.66 mmol) and refluxed in the dark for 1h. The mixture, containing 2-acetoxybenzoyl isocyanate, was cooled to RTand used in the next step.

Step 3: To the above mixture was added a solution of LI-2b (1.33 g, 6.66mmol) in benzene (5 mL) and stirred at RT for 1 h. The mixture wasfiltered through celite and concentrated, and the residue was purifiedby column chromatography to afford 1.2 g (54%) of pure I-C1-NOPD5a.¹H-NMR data is consistent with the expected structure. MS (ES⁺) m/z:404.98 [M+H]⁺, 426.94 [M+Na]⁺, 442.97 [M+K]⁺, (ES⁻) m/z: 403.01 [M−H]⁻.

Example 85 Synthesis of Sodium Salt of NO-Releasing Prodrug of Aspirin(I-C1-NOPD5b)

To a suspension of 60% sodium hydride (45 mg, 1.3 mmol) in THF (0.5 mL)was added solution of I-C1-NOPD5a (500 mg, 1.24 mmol) in THF (1.5 mL).After stirring for 5 min, THF was removed under vacuum, the residue waswashed with dry Et₂O (4×3 mL) to remove unreacted starting material anddried in vacuum to afford 410 mg (78%) of I-C1-NOPD5b as an off-whitesolid. ¹H NMR (D₂O, 500 MHz): δ 2.28 (s, 3H), 2.93-2.97 (m, 4H), 4.33(t, 2H, J=6.0 Hz), 4.68 (t, 2H, J=7.2 Hz), 7.07 (d, 1H, J=8.0 Hz), 7.26(t, 1H, J=7.5 Hz), 7.41 (t, 1H, J=9.0 Hz), 7.57 (d, 1H, J=7.5 Hz). MS:m/z 427.0 [M+H]⁺, 449.0 [M+Na]⁺.

Example 86 Synthesis of NO-Releasing Prodrug of Aspirin (I-C1-NOPD6)

This prodrug was synthesized as shown in Scheme 11, Method E. Thus, to asolution of aspirin (1.20 g, 6.70 mmol) in DCM (15 mL) at 0° C. wasadded oxalyl chloride (0.74 mL, 8.65 mmol) and stirred at RT for 1.5 h.The mixture was concentrated and the residual acid chloride was treatedwith LI-5.TFA (6.70 mmol) in DCM (14 mL), followed by drop-wise additionof TEA (3.73 mL, 26.81 mmol) at 0° C. The mixture was stirred at RT for4 h and concentrated. The residue, after usual aqueous work-up andchromatographic purification, gave 0.822 g (34%) of I-C1-NOPD6. ¹H-NMR(300 MHz, CDCl₃): δ 2.35 (s, 3H), 2.92 (t, 2H, J=6.11 Hz), 2.98 (t, 2H,J=6.0 Hz), 3.76 (q, 2H, J=6.0 Hz), 4.71 (t, 2H, J=6.0 Hz), 6.70 (bs,1H), 7.10 (d, 1H, J=9.0 Hz), 7.31-7.33 (m, 1H), 7.48-7.50 (m, 1H), 7.78(d, 1H, J=6.0 Hz). MS (EI)⁺ m/z: 361 (M+H)⁺.

Example 87 Synthesis of NO-Releasing Prodrug of Nicotinic Acid(I-C1-NOPD7)

This prodrug was synthesized as shown in Scheme 11, Method C. Thus, to asuspension of nicotinyl chloride hydrochloride (2.68 g, 15.07 mmol) inTHF (10 mL) at 0° C. was added a solution of LI-2b (2.0 g, 10.05 mmol)and TEA (5.6 mL, 40.2 mmol) in THF (7 mL) and stirred at RT for 15 h.The mixture was filtered, concentrated and the residue purified bycolumn chromatography to afford 2.23 g (73%) of pure I-C1-NOPD7. ¹H-NMR(300 MHz, CDCl₃): δ 3.01 (t, 2H, J=4.75 Hz), 3.09 (t, 2H, J=6.5 Hz),4.63 (t, 2H, J=5.25 Hz), 4.70 (t, 2H, J=4.75 Hz), 7.39-7.42 (m, 1H),8.29-8.31 (dt, 1H, J=8 Hz, 2 Hz), 8.78-8.80 (dd, 1H, J=2 Hz), 9.23 (d,1H, J=2 Hz). MS (ES)⁺ m/z: 305 (M+H)⁺.

Example 88 Synthesis of NO-Releasing Prodrug of Nicotinamide(I-C1-NOPD8a)

This prodrug was synthesized from nicotinamide (1 g, 8.18 mmol)according to the procedure described in Example 77 (see Scheme 11,Method I or Scheme 13, Method A). After usual workup, the crude productwas purified by column chromatography to afford 0.1 g (3.5%) of prodrugI-C1-NOPD8a. ¹H-NMR (300 MHz, CDCl₃): δ 2.97-3.0 (m, 4H), 4.51 (t, 2H,J=6.3 Hz), 4.73 (t, 2H, J=6.7 Hz), 7.38-7.48 (m, 1H), 8.16-8.22 (m, 1H),8.71-8.79 (m, 2H), 9.04 (s, 1H). MS [ES]⁺ m/z: 348 [M+H]⁺, 370 [M+Na]⁺.

Example 89 Synthesis of NO-Releasing Prodrug of Nicotinic Acid(I-C1-NOPD9)

This prodrug was synthesized as shown in Scheme 11, Method F. Thus, TEA(6.92 mL, 50.55 mmol) was added to a suspension of nicotinyl chloridehydrochloride (3.0 g, 16.85 mmol) and cysteamine hydrochloride (2.11 g,18.53 mmol) in DCM (30 mL) at 0° C. and stirred at RT for 4 h. Themixture was concentrated and the residue dissolved in MeOH (20 mL). Tothis solution at 0° C. was added a solution of LI-3b (4.11 g, 16.85mmol) in MeOH (5 mL), followed by TEA (4.61 mL, 33.70 mmol) and stirredovernight at RT. The mixture was filtered through celite, concentratedand the residue was purified by column chromatography to afford 3 g(58%) of pure I-C1-NOPD9. ¹H-NMR (300 MHz, DMSO-d₆): 2.94 (t, 2H, J=6.7Hz), 3.09 (t, 2H, J=6.3 Hz), 3.56 (q, 2H, J=6.3 Hz), 4.73 (t, 2H, J=6.3Hz), 7.49-7.53 (m, 1H), 8.16-8.19 (m, 1H), 8.69-8.70 (m, 1H), 8.87 (brt, 1H), 8.98 (s, 1H). MS (ES⁺) m/z: 304 (M+H)⁺, 326 (M+Na)⁺.

Example 90 Synthesis of NO-Releasing Prodrug of Naproxen (I-C1-NOPD10)

This prodrug was synthesized as shown in Scheme 11, Method B. Thus, to asolution of naproxen (2.23 g, 9.7 mmol) and LI-2b (1.93 g, 9.7 mmol) inTHF (70 mL) at RT were added DCC (3 g, 14.55 mmol) and DMAP (1.78 g,14.55 mmol) and stirred overnight. The mixture was filtered andconcentrated, and the residue purified by column chromatography toafford 1.03 g (25%) of pure I-C1-NOPD10. ¹H-NMR (300 MHz, CDCl₃): δ 1.59(d, 3H, J=7.16 Hz), 2.81 (t, 2H, J=6.77 Hz), 2.87 (t, 2H, J=6.42 Hz),3.85-3.88 (m, 1H), 3.91 (s, 3H), 4.33 (t, 2H, J=5.26 Hz), 4.53 (t, 2H,J=6.79 Hz), 7.10-7.16 (m, 2H), 7.41 (d, 1H, J=1.7 Hz), 7.69 (t, 3H,J=8.55 Hz).

Example 91 Synthesis of NO-Releasing Prodrug of Naproxen (I-C1-NOPD12)

This prodrug was synthesized as shown in Scheme 11, Method E. Thus, to asolution of naproxen (1.698 g, 7.37 mmol) in chloroform (20 mL) at 0-5°C. was added oxalyl chloride (0.8 mL, 8.844 mmol), followed by 2-3 dropsof DMF. The mixture was stirred at RT for 90 min and concentrated. Thisacid chloride (˜7.37 mmol) was treated with LI-5.TFA (6.7 mmol) in THF(20 mL) and cooled to 0° C. To this was added TEA (5.6 mL, 40 mmol) andstirred at RT for 3 h. The mixture was concentrated and the residue,after usual aqueous work-up and chromatographic purification, afforded0.409 g (14%) of pure I-C1-NOPD12. ¹H-NMR (CDCl₃, 300 MHz): δ 1.24 (d,3H), 2.87 (t, 2H, J=6.5 Hz), 2.93 (t, 2H, J=6.7 Hz), 3.64 (q, 2H, 7.5Hz), 3.76 (m, 1H), 3.88 (s, 3H), 4.70 (t, 2H, J=6.6 Hz), 4.79 (br s,1H), 6.97-7.08 (m, 3H), 7.35-7.46 (m, 3H).

Example 92 Synthesis of NO-Releasing Prodrug of Flurbiprofen(I-C1-NOPD13)

This prodrug was synthesized as shown in Scheme 11, Method A, using asreagents flurbiprofen (4.0 g, 16.37 mmol), CDI (3.97 g, 24.56 mmol) andLI-2b (3.25 g, 16.37 mmol). Yield: 3 g (43%). ¹H-NMR (300 MHz, CDCl₃): δ1.56 (d, 3H, J=7.2 Hz), 2.80-3.0 (m, 4H, J=5.67 Hz), 3.78 (q, 1H, J=7.10Hz), 4.36 (m, 2H), 4.66 (t, 2H, J=6.78), 7.11-7.54 (m, 8H).

Example 93 Synthesis of NO-Releasing Prodrug of Flurbiprofen(I-C1-NOPD14a)

This prodrug was synthesized as shown in Scheme 11, Method I. Thus, to asolution of flurbiprofen (5.0 g, 20.46 mmol) in benzene (50 mL), wasadded oxalyl chloride (3.11 g, 24.55 mmol) at 0° C. and 2 drops of DMFand stirred at RT for 20 hrs. Benzene was removed under vacuum and theresidue was diluted with DCM (50 mL). The reaction mixture was cooled to0° C. and dry ammonia was passed for 30 min. The reaction mixture wasconcentrated and, after usual aqueous work-up, 4.5 g of flurbiprofenamide was obtained as a white solid.

To a solution of flurbiprofen amide (3.0 g, 12.33 mmol) in DCM (70 mL)was added oxalyl chloride (1.87 g, 14.79 mmol) at 0° C. and refluxed for16 h. Reaction mixture was cooled to RT and treated with LI-2b (2.45 g,12.33 mmol) in DCE (10 mL) and stirred overnight. After usual aqueouswork-up and chromatographic purification, 0.5 g of I-C1-NOPD14a wereobtained. ¹H NMR (CDCl₃, 300 MHz): δ 1.55 (d, 3H, J=6.9 Hz), 2.94-2.97(bs, 4H), 4.38-4.47 (bs, 3H), 4.68 (t, 2H, J=6.6 Hz), 7.13-7.55 (bs, 8H)MS: ES⁺ m/z 469.03 [M+H]⁺, 467.16 [M−H]⁺.

Example 94 Synthesis of NO-Releasing Prodrug of Flurbiprofen(I-C1-NOPD15b)

This prodrug was synthesized as shown in Scheme 11, Method A. Thus, to asolution of flurbiprofen (2.5 g, 10.23 mmol) in THF (30 mL) was addedCDI (3.31 g, 20.46 mmol) and stirred at RT for 16 h. To this was addedLI-5.TFA (3.64 g, 10.23 mmol) in THF (15 mL), followed by TEA (2.85 mL,20.46 mmol) and stirred for 16 h. After usual work-up andchromatographic purification, 1.5 g (91%) of I-C1-NOPD15b were obtained.¹H NMR (CDCl₃, 300 MHz): δ 1.5 (d, 3H, J=6.9 Hz), 2.82 (t, 2H, J=6.3Hz), 2.92 (t, 2H, J=6.9 Hz), 3.50 (m, 3H), 4.6 (t, 2H, J=6.6 Hz), 5.8(s, 1H), 7.11-7.55 (bs, 8H). MS: ES⁺ m/z 425.21 [M+H]⁺, 423.11 [M−H]⁻.

Example 95 Synthesis of NO-Releasing Prodrug of Indomethacin(I-C1-NOPD16)

This prodrug was synthesized as shown in Scheme 11, Method A. Thus, to asolution of indomethacin (2.0 g, 5.59 mmol) in chloroform (25 mL) wasadded CDI (1.09 g, 6.71 mmol) and stirred for 2 h. A solution of LI-2b(1.22 g, 6.15 mmol) and DMAP (751 mg, 6.15 mmol) in chloroform (5 mL)was added, and the mixture was stirred at RT for 16 h. After usualaqueous work-up and chromatographic purification, 2.02 g (67%) of pureI-C1-NOPD16 was obtained. ¹H-NMR (300 MHz, CDCl₃): δ 2.39 (s, 3H),2.88-2.95 (m, 4H), 3.69 (s, 2H), 3.84 (s, 3H), 4.38 (t, 2H, J=6.3 Hz),4.63 (t, 2H, J=6.6 Hz), 6.67 (dd, 1H, J=2.4, 8.7 Hz), 6.87 (d, 1H, J=8.7Hz), 6.96 (d, 1H, J=2.1 Hz), 7.47 (d, 2H, J=8.4 Hz), 7.67 (d, 2H, J=8.4Hz). MS (ES⁺) m/z: 539.2 [M+H]⁺, 560.79 [M+Na]⁺.

Example 96 Synthesis of NO-Releasing Prodrug of Indomethacin(I-C1-NOPD18)

This prodrug was synthesized as shown in Scheme 11, Method A. Thus, to asolution of indomethacin (3.01 g, 8.42 mmol) in THF (50 mL) at RT wasadded CDI (1.64 g, 10.10 mmol). After 1 h, LI-5.TFA (3 g, 8.42 mmol) wasadded at 0° C., followed by TEA (5.9 mL, 42.1 mmol) and DMAP (0.6 g,4.91 mmol). The reaction mixture was stirred at RT for 2 d. After usualaqueous work-up and chromatographic purification, 3.16 g (70%) ofI-C1-NOPD18 were obtained as yellow solid. ¹H NMR (CDCl₃, 300 MHz): δ2.38 (s, 3H), 2.79 (t, 2H, J=6.3 Hz), 2.86 (t, 2H, J=6.9 Hz), 3.54 (q,2H, J=6.0 Hz), 3.66 (s, 2H), 3.83 (s, 3H), 4.61 (t, 2H, J=6.6 Hz), 6.01(bs, 1H), 6.71 (dd, 1H, J=2.1, 9.0 Hz), 6.9 (dd, 2H, J=3.3, 8.1 Hz),7.49 (d, 2H, J=8.4 Hz, 2H), 7.66 (d, 2H, J=8.4 Hz). MS: m/z 538.10[M+H]⁺, 560.1 [M+Na]⁺.

Example 97 Synthesis of NO-Releasing Prodrug of Ketoprofen (I-C1-NOPD19)

This prodrug was synthesized as shown in Scheme 11, Method A accordingto the method described in Example 90, using as reagents ketoprofen(1.27 g, 5 mmol), CDI (1.21 g, 7.5 mmol) and LI-2b (1 g, 5 mmol). Yield:0.6 g (51%). ¹H-NMR (300 MHz, CDCl₃): δ 1.55 (d, 3H; J=7.0 Hz),2.80-2.95 (m, 4H), 3.82 (q, 1H, J=6.7 Hz), 4.35 (t, 2H, J=6.1 Hz), 4.64(t, 2H, J=6.5 Hz), 7.40-7.85 (m, 9H). MS (ES⁺) m/z: 436.06 [M+H]⁺,458.02 [M+Na]⁺.

Example 98 Synthesis of NO-Releasing Prodrug of Ketoprofen(I-C1-NOPD20a)

This prodrug was synthesized as shown in Scheme 11, Method I. Thus, to asolution of the amide of ketoprofen (1.78 g, 7 mmol) in DCE (70 mL) wasadded oxalyl chloride (1.0 g, 8.4 mmol) at 0° C. and refluxed for 16 h.After cooling to RT, a solution of LI-2B (1.4 g, 7 mmol) in DCE (10 mL)was added and stirred for 20 h. After usual aqueous work-up andchromatographic purification, 0.6 g (17%) of I-C1-NOPD20a was obtainedas a pale yellow gum. ¹H NMR (CDCl₃, 300 MHz): δ 1.47 (d, 3H, J=6.96Hz), 3.00 (bs, 4H), 4.00 (q, 1H, J=6.81 Hz), 4.39 (t, 2H, J=6.21 Hz),4.68 (bs, 2H), 7.47-7.77 (bs, 9H). MS: ES⁺ m/z 478 [M+H]⁺, 477.15[M−H]⁺.

Example 99 Synthesis of NO-Releasing Prodrug of Diclofenac (I-C1-NOPD22)

This prodrug was synthesized as shown in Scheme 11, Method B, using asreagents diclofenac (1.0 g, 3.378 mmol), LI-2b (0.68 g, 3.37 mmol), DMF(8 mL), DCC (0.835 g, 4.054 mmol) and DMAP (0.082 g, 0.675 mmol). Yield:0.35 g (22%). ¹H-NMR (300 MHz, CDCl₃): δ 2.91-3.04 (m, 4H), 3.85 (s,2H), 4.42 (t, 2H, J=6.6 Hz), 4.72 (t, 2H, J=6.6 Hz), 6.56 (d, 1H, J=8.1Hz), 6.82 (s, 1H), 6.94-7.03 (m, 2H), 7.12-7.27 (m, 2H), 7.35 (d, 1H,J=8.1 Hz). MS (ES⁺) m/z: 476.90 [M+H]⁺, 498.86 [M+Na]⁺.

Example 100 Synthesis of NO-Releasing Prodrug of Flurbiprofen(I-C1-NOPD26)

This prodrug was synthesized as outlined in Scheme 20. Thus, to asolution of S20-I1 (0.8 g, 2.90 mmol) in THF (10 mL) and DMF (10 mL) wasadded the cesium salt of flurbiprofen (1.2 g, 3.19 mmol) and stirred atRT for 2 h. After usual aqueous work-up and chromatographicpurification, 1.13 g (80%) of I-C1-NOPD26 was obtained as a light yellowsemi solid. ¹H NMR (500 MHz, CDCl₃): δ 1.58 (d, 3H, J=7.5 Hz), 2.88-2.94(m, 4H), 3.88 (q, 1H, J=7.0 Hz), 4.40 (t, 2H, J=6.5 Hz), 4.64-4.68 (m,4H), 7.14-7.54 (m, 8H). MS: m/z 501.1 [M+NH₄]⁺, 506.1 [M+Na]⁺.

Example 101 Synthesis of NO-Releasing Prodrug of Gabapentin Ethyl Ester(I-A1-NOPD1)

This prodrug was synthesized as shown in Scheme 12, Method A. Thus, to astirred solution of diphosgene (0.88 mL, 7.37 mmol) in DCM (3 mL) at 0°C. was added drop-wise a solution of LI-2a (0.80 g, 3.68 mmol) & Hunig'sbase (1.92 mL, 11.85 mmol) in DCM (1 mL). The mixture was stirred at 0°C. for 30 min and concentrated. The residue was dissolved in DCM (4 mL)and treated with gabapentin ethyl ester hydrochloride (0.95 g, 4.05mmol) & Hunig's base (1.39 mL, 8.05 mmol). The mixture was stirred at RTfor 3 h and concentrated. The residue, after usual aqueous work-up, gave1.6 g (98%) of I-S12-I1. ¹H-NMR data is consistent with the expectedstructure. MS (ES⁺) m/z: 444 [M+H]⁺, 465.9 [M+Na]⁺.

To a stirred solution of I-S12-I1 (1.3 g, 2.94 mmol) in acetonitrile (8mL) at RT was added silver nitrate (0.6 g, 3.52 mmol) portion-wise andstirred at RT for 2.5 h. After filtration through celite, the filtratewas concentrated and the residue purified by column chromatography toafford 0.561 g (45%) of prodrug I-A1-NOPD1. ¹H-NMR data is consistentwith the expected structure. MS (ES⁺) m/z: 425 (M+H)⁺, 447 (M+Na)⁺.

Example 102 Synthesis of NO-Releasing Prodrug of Lamotrigine(I-A1-NOPD3a and I-A1-NOPD3b)

This prodrug was synthesized as shown in Scheme 12, Method B. Thus, to asuspension of lamotrigine (1 g, 3.90 mmol) in toluene (20 mL) at 120° C.was added drop-wise a solution of the imidazolide of LI-2b (1.4 g, 4.70mmol) in THF (10 mL) and refluxed for 6 h. After usual aqueous work-upand chromatographic purification, 340 mg (20%) of I-A1-NOPD-3a/b wasobtained. ¹H-NMR data is consistent with the expected structure. MS(ES)⁺ m/z: 481 (M+H)⁺.

Example 103 Synthesis of NO-Releasing Prodrug of Nicotinic Hydrazide(I-A1-NOPD4)

This prodrug was synthesized from nicotinic hydrazide (235 mg, 1.70mmol) according to the procedure described in Example 109 (see Scheme13, Method B). After usual workup, the crude product was purified bycolumn chromatography to afford 0.21 g (34%) of prodrug I-A1-NOPD4.¹H-NMR (300 MHz, DMSO-d₆): δ 3.02 (t, 2H, J=5.8 Hz), 3.10 (t, 2H, J=6.1Hz), 4.28 (t, 2H, J=5.8 Hz), 4.76 (t, 2H, J=6.1 Hz), 7.51-7.55 (dd, 1H,J=4.8 Hz, 7.7 Hz), 8.17 (d, 1H, J=7.8 Hz), 8.74 (d, 1H, J=3.8 Hz), 8.98(s, 1H), 9.44 (bs, 1H), 10.54 (bs, 1H). MS (EI)⁺ m/z: 363 [M+H]⁺.

Example 104 Synthesis of NO-Releasing Prodrug of Lisinopril DimethylEster (I-A1-NOPD5)

This prodrug was synthesized from lisinopril dimethyl esterhydrochloride (1.10 g, 2.56 mmol) according to the procedure describedin Example 101 (see Scheme 12, Method B). After usual workup, the crudeproduct was purified by column chromatography to afford 0.76 g (67%) ofprodrug I-A1-NOPD5. ¹H-NMR (300 MHz, CDCl₃): δ 1.49-1.54 (m, 2H),1.93-2.07 (m, 8H), 2.12-2.28 (m, 1H), 2.64-2.68 (m, 2H), 2.91-3.0 (m,4H), 3.18-3.25 (m, 3H), 3.42-3.47 (m, 1H), 3.52-3.55 (m, 2H), 3.69 (s,3H), 3.73 (s, 3H), 4.28 (t, J=6.3 Hz, 2H), 4.47-5.05 (m, 1H), 4.69 (t,J=6.8 Hz, 2H), 5.22 (bt, 1H), 7.14-7.19 (m, 3H), 7.23-7.28 (m, 2H). MS(EI)⁺ m/z: 659 [M+H]⁺.

Example 105 Synthesis of NO-Releasing Prodrug of Omeprazole (I-A1-NOPD6)

This prodrug was synthesized as shown in Scheme 12, Method B. To anice-cold solution of diphosgene (0.3 mL, 2.48 mmol) in toluene at 0° C.,was added a mixture of LI-2b (0.5 g, 2.51 mmol) and TEA (0.42 mL, 3.0mmol) in toluene (3 mL) and stirred for 2 h. In a separate flask,omeprazole (0.867 g, 2.50 mmol) was dissolved in THF (5 mL), cooled to0° C. and NaH (0.059 g, 2.5 mmol) was added. The mixture was stirred for30 min, the above reaction mixture was added dropwise to it and stirredfor 2 h. After usual aqueous work-up and chromatographic purification,0.23 g (20%) of I-A1-NOPD6 was obtained as a reddish-yellow gum. MS:ES+m/z 571 (M+H)⁺, 593 (M+Na)⁺.

Example 106 Synthesis of NO-Releasing Prodrug of Hydralazine(I-A1-NOPD7)

This prodrug was synthesized from hydralazine hydrochloride (0.99 g,5.01 mmol) according to the procedure described in Example 109 (seeScheme 13, Method B). After usual workup, the crude product was purifiedby column chromatography to afford 0.8 g (41%) of prodrug I-A1-NOPD7.¹H-NMR (300 MHz, CDCl₃): δ 2.95-3.06 (m, 4H), 4.43 (t, 2H, J=6.35 Hz),4.69 (t, 2H, J=6.7 Hz), 7.57 (m, 1H), 7.63-7.71 (m, 2H), 8.16 (s, 1H),8.29 (d, 1H, J=7.6 Hz). MS (ES⁺) m/z: 386.05 (M+H)⁺.

Example 107 Synthesis of NO-Releasing Prodrug of Amlodipine (I-A1-NOPD8)

This prodrug was synthesized from amlodipine (1.67 g, 4.09 mmol)according to the procedure described in Example 109 (see Scheme 12,Method B). After usual workup, the crude product was purified by columnchromatography to afford 1.33 g (61%) of I-A1-NOPD8. ¹H-NMR (300 MHz,CDCl₃): δ 1.18 (t, 3H, J=7.1 Hz), 2.36 (s, 3H), 2.93-2.99 (m, 4H), 3.47(bs, 2H), 3.61-3.64 (m, 5H), 4.04 (q, 2H, J=7.1 Hz), 4.35 (bt, 2H),4.68-4:74 (m, 4H), 5.0 (bs, 1H), 7.13-7.36 (m, 4H). MS (ES⁺) m/z: 634.14(M+H)⁺, 656.83 (M+Na)⁺; (ES⁻) m/z: 631.94 (M−H)⁺.

Example 108 Synthesis of NO-Releasing Prodrug of Levetiracetam(I-A2-NOPD1a)

This prodrug was synthesized from levetiracetam (1.0 g, 5.87 mmol)according to the procedure generally described in Example 82 (see Scheme13, Method A). After usual workup and chromatographic purification, theproduct was further purified by preparative HPLC to afford 728 mg (31%)of prodrug I-A2-NOPD1a. ¹H-NMR was consistent with the expectedstructure. MS (ES)⁺ m/z: 396.1 [M+H]⁺, 418.1 [M+Na]⁺, (ES)⁻ m/z: 394.1[M−H]⁻.

Example 109 Synthesis of NO-Releasing Prodrug of Valdecoxib(I-A3-NOPD1a)

This prodrug was synthesized as shown in Scheme 13, Method B. Thus, to acold suspension of sodium hydride (271 mg, 6.81 mmol) in THF (7 mL) wasadded drop-wise a solution of valdecoxib (1.78 g, 5.68 mmol) in THF (15mL) and stirred at RT for 2 h. A solution of the imidazolide of LI-2b(2.0 g, 6.81 mmol) in THF (15 mL) was added and stirred at roomtemperature for 18 h. The reaction mixture was concentrated and theresidue, after usual aqueous work-up and chromatographic purification,afforded 976 mg (32%) of prodrug I-A3-NOPD1a. ¹H-NMR data is consistentwith the expected structure. MS (ES)⁻ m/z: 538 [M−H]⁻.

Example 110 Synthesis of NO-Releasing Prodrug of Celecoxib (I-A3-NOPD2a)

This prodrug was synthesized from celecoxib (6.62 g, 17.35 mmol)according to the procedure described in Example 109 (see Scheme 13,Method B). After usual workup, the crude product was purified by columnchromatography to afford 1.55 g (15%) of prodrug I-A3-NOPD2a. ¹H-NMR(300 MHz, CDCl₃): δ 2.38 (s, 3H), 2.84-2.98 (m, 4H), 4.34 (t, 2H, J=6.45Hz), 4.63-4.71 (m, 2H), 6.74 (s, 1H), 7.09-7.25 (m, 4H), 7.51 (d, 2H,J=6.8 Hz), 8.02 (d, 2H, J=6.8 Hz). MS (ES)⁺ m/z: 606.87 [M+H]⁺, 628.93[M+Na]⁺; (ES)⁻ m/z: 604.88 [M−H]⁻.

Example 111 Synthesis of NO-Releasing Prodrug of Paracetamol(I-H1-NOPD1)

This prodrug was synthesized as shown in Scheme 14, Method B. Thus, to asolution of paracetamol (2.0 g, 13.24 mmol) in THF (20 mL) was added CDI(2.36 g, 14.57 mmol) and the mixture was stirred at RT for 3 h. To thiswas added a solution of LI-2b (1.21 g, 6.62 mmol), followed by DMAP(0.802 g, 6.622 mmol) and stirred overnight at RT. The mixture wasquenched with water and extracted with EtOAc. After usual aqueouswork-up and chromatographic purification, 0.3 g (6%) of prodrugI-H1-NOPD1. ¹H-NMR data is consistent with the expected structure. MS(CI)⁺ m/z: 376 [M+H]⁺.

Example 112 Synthesis of NO-Releasing Prodrug of Paracetamol(I-H1-NOPD2a)

This prodrug was synthesized as shown in Scheme 14, Method D. Thus, to asolution of chlorocarbonyl isocyanate (0.701 g, 6.622 mmol) in benzene(5 mL) at 0° C. was added a solution of paracetamol (1 g, 6.622 mmol)and stirred at 0° C. for 1 h. To this was added a solution of LI-2b(1.21 g, 6.622 mmol) and TEA (1 mL) in THF (5 mL), and stirred overnightat RT. After usual aqueous work-up and chromatographic purification, 90mg (3%) of prodrug I-H1-NOPD2a was obtained. ¹H-NMR data was consistentwith the expected structure. MS: (ES)⁻ m/z: 418 [M−H]⁻.

Example 113 Synthesis of NO-Releasing Prodrug of Paracetamol(I-H1-NOPD3)

This prodrug was synthesized from paracetamol (2.0 g, 13.24 mmol)according to the procedure described in Example 122 (see Scheme 14,Method C). After usual workup, the crude product was purified by columnchromatography to afford 1.0 g (20%) of prodrug I-H1-NOPD3. ¹H-NMR (500MHz, CDCl₃): δ 2.11 (s, 3H), 2.91 (t, 2H, J=6.5 Hz), 3.06 (t, 2H, J=6.5Hz), 3.49 (t, 2H, J=6.5 Hz), 4.75 (t, 2H, J=6.5 Hz), 7.05 (d, 2H, J=9.0Hz), 7.54 (d, 2H, J=9.0 Hz). MS (ES)⁺ m/z: 376 [M+H]⁺, 393 [M+NH₄]⁺, 397[M+K]⁺.

Example 114 Synthesis of NO-Releasing Prodrug of Metronidazole(I-H1-NOPD6)

This prodrug was synthesized in two steps as shown in Scheme 14, MethodC.

Step 1: To a suspension of metronidazole (5 g, 29.22 mmol) in chloroform(100 mL) was added CDI (5.21 g, 32.2 mmol) and stirred overnight at RT.The reaction mixture, after usual aqueous work-up, gave 7.66 g (98%) ofthe imidazolide intermediate. ¹H-NMR data was consistent with theexpected structure. MS (ES)⁺ m/z: 266.1 [M+H]⁺.

Step 2: To a mixture of LI-5.TFA (2.68 mmol) and TEA (1.08 g, 10.72mmol) in DCM (10 mL) at 0° C. was added the imidazolide of metronidazole(0.78 g, 2.95 mmol) and stirred at RT for 48 h. The reaction mixture wasquenched with water and extracted with DCM. After usual aqueous work-upand chromatographic purification, 50 mg (4.3%) of I-H1-NOPD6 wasobtained. ¹H-NMR (500 MHz, CDCl₃): δ 2.50 (s, 3H), 2.80 (t, 2H, J=6.3Hz), 2.96 (t, 2H, J=6.6 Hz), 3.47-3.50 (m, 2H), 4.41 (t, 2H, J=5.1 Hz),4.58 (t, 2H, J=5.1 Hz), 4.70 (t, 2H, J=6.6 Hz), 7.96 (s, 1H). MS (ES)⁺m/z: 395.99 [M+H]⁺.

Example 115 Synthesis of NO-Releasing Prodrug of Budesonide (I-H1-NOPD9)

This prodrug was synthesized from budesonide (0.5 g, 1.16 mmol)according to the procedure described in Example 122 (see Scheme 14,Method C). After usual workup, the crude product was purified by columnchromatography to afford 0.25 g (33%) of prodrug I-H1-NOPD9. ¹H-NMR datawas consistent with the expected structure. MS (ES)⁺ m/z: 655 [M+H]⁺.

Example 116 Synthesis of NO-Releasing Prodrug of 4-Hydroxy-TEMPO(I-H1-NOPD10)

A solution of LI-2b (0.20 g, 1.20 mmol) and CDI (0.195 g, 1.20 mmol) inchloroform (5 mL) was stirred at RT for 2 h, which was followed by theaddition of 4-hydroxy-TEMPO (0.173 g, 1.00 mmol) and DMAP (0.122 g, 1.00mmol). The mixture was refluxed for 2 d, then purified by columnchromatography to afford 110 mg (27%) of I-H1-NOPD10 as a red oil. MS:EI+ m/z 398 [M+H]⁺, 420 [M+Na]⁺.

Example 117 Synthesis of NO-Releasing Prodrug of Edaravone (I-H1-NOPD11)

To a solution of edaravone (0.87 g, 5 mmol) in acetonitrile was addedKF—Al₂O₃ (66 g) and, under thorough mixing, LI-3a (2.8 g, 10 mmol) wasadded. The mixture was agitated for 20 h. After usual aqueous work-upand chromatographic purification, 70 mg (4%) of the intermediate bromidewas obtained as a reddish-yellow oil. ¹H NMR (CDCl₃, 500 MHz): δ 2.28(s, 3H), 3.00-3.10 (m, 4H), 3.59 (t, 2H, J=8 Hz), 4.34 (t, 2H, J=6.5Hz), 5.5 (s, 1H), 7.4 (t, 2H, J=1 Hz), 7.69 (t, 3H, J=1 Hz). MS: ES⁺ m/z375 [M+H]⁺, 397.0 [M+Na]⁺.

To a solution of the above bromide (0.05 g, 0.134 mmol) in acetonitrile(1.5 mL) was added AgNO₃ (0.027 g, 0.160 mmol) and stirred for 20 h.After usual aqueous workup and purification, 0.025 g (53%) ofI-H1-NOPD11 was obtained as a brown gum. ¹H NMR (CDCl₃, 500 MHz): δ 2.28(s, 3H), 2.90 (t, 2H, J=6.5 Hz), 3.10 (t, 2H, J=6.5 Hz), 4.33 (t, 2H,J=6.0 Hz), 4.63 (t, 2H, J=6.5 Hz), 5.5 (s, 1H), 7.60-7.63 (bs, 2H),7.65-7.67 (bs, 3H). MS: ES⁺ m/z 356 [M+H]⁺.

Biological Example 1 Screening of Prodrugs and Mutual Prodrugs ofAnticonvulsants

Most of the prodrugs and mutual prodrugs of anticonvulsants described inthis invention were evaluated at National Institute of NeurologicalDisorders and Stroke (NINDS), National Institute of Health (NIH), undertheir Antiepileptic Screening Program (ASP).

Test 1 is an initial screening for anticonvulsant activity in theMaximal Electroshock Test (MES) and Subcutaneous Metrazol SeizureThreshold Test (scMET) models combined with an initial assessment oftoxicity (TOX) in mice via i.p. injection (see further explanationbelow). The data for each condition is presented as N/F, where N=numberof animals protected from seizure and F=number of animals tested. Fortest of toxicity, N=number of animals displaying toxic effects andF=number of animals tested. Any deaths occurring during the test wererecorded.

Maximal Electroshock Test (MES): The MES is a model for generalizedtonic-clonic seizure and provides an indication of a compound's abilityto prevent seizure spread when all neuronal circuits in the brain aremaximally active. These seizures are highly reproducible andelectro-physiologically consistent with human seizures. For all testsbased on MES convulsions, 60 Hz of alternating current (50 mA in mice)is delivered for 2 s by corneal electrodes, which have been primed withan electrolyte solution containing an anesthetic agent (0.5% tetracainehydrochloride). Mice were tested at various intervals following doses of30, 100 and 300 mg/kg of test compound given by i.p. injection of avolume of 0.01 mL/g. Other doses can be used if indicated by previouslyknown pharmacology. An animal is considered “protected” from MES-inducedseizures upon abolition of the hind-limb tonic extensor component of theseizure.

Subcutaneous Metrazol Seizure Threshold Test (scMET): Subcutaneousinjection of the convulsant metrazol produces clonic seizures inlaboratory animals. The scMET test detects the ability of the testcompound to raise the seizure threshold of an animal and thus protect itfrom exhibiting a clonic seizure. Animals were pretreated with variousdoses of the test compound given by i.p. injection. At the previouslydetermined Time to Peak Effect (TPE) of the test compound, the dose ofmetrazol which will produce convulsions in 97% of animals (CD₉₇: 85mg/kg in mice) was injected into a loose fold of skin in the midline ofthe neck. The animals were placed in isolation cages to minimize stressand observed for the next 30 minutes for the presence or absence of aseizure. An episode of clonic spasms, approximately 305 seconds, of thefore and/or hind limbs, jaws, or vibrissae is taken as the end point.Animals which do not meet this criterion were considered protected.

Acute Toxicity—Minimal Motor Impairment (MMI): To assess a compound'sundesirable side effects (toxicity), animals were monitored for overtsigns of impaired neurological or muscular function. In mice, therotorod procedure is used to disclose minimal muscular or neurologicalimpairment. When a mouse is placed on a rod that rotates at a speed of 6rpm, the animal can maintain its equilibrium for long periods of time.The compound is considered toxic if the animal falls off this rotatingrod three times during a 1-min period. In addition to MMI, animals mayexhibit a circular or zigzag gait, abnormal body posture and spread ofthe legs, tremors, hyperactivity, lack of exploratory behavior,somnolence, stupor, catalepsy, loss of placing response and changes inmuscle tone.

Compounds that were active in Test 1 (mice i.p.) were further screenedin Test 2 (rat p.o.). Compounds retaining activity in Test 2 (rat p.o.)were selected for secondary evaluation (i.e., Test 3, Rat P.O.quantification) as explained below:

Secondary Evaluation: All quantitative in vivo anticonvulsant/toxicityevaluations of the active compounds were conducted at compound's time ofpeak pharmacodynamic activity (TPE). Groups of at least 8 rats receivedvarious doses of the candidate compound until at least two points wereestablished between the limits of 100 percent protection or toxicity andzero percent protection or minimal toxicity. The 95 percent confidencelimits, slopes of the regression lines and standard errors of the slopeswere calculated for each quantitative determination. Rats received testcompounds orally.

Test 1 screening results are presented in Table 1. Compound I-CA-MPD24was active in both MES and scMET models and was shown to be non-toxic.However, some compounds were active in both MES and scMET models andwere also shown to be toxic. The compounds (i.e., I-A1-PD4, I-AA-MPD12,I-CA-MPD23, I-A1-PD5, I-A1-NOPD3, I-CA-MPD24, I-A1-PD15, I-CA-MPD25, andI-AA-MPD11) that are shown to be active in MES but showed no or mildtoxicity were selected for Test 2 screening and those results arepresented in Table 2.

Three of the compounds (i.e., I-A1-PD4, I-AA-MPD12, and I-A1-NOPD3) wereconsidered for secondary evaluation, where quantification of theirantiepileptic activity and neurotoxicity in rats (p.o.) was carried out.This secondary evaluation determines the time to peak effect (TPE),neurotoxicity, median effective dose (ED₅₀) and biological response. The95% confidence interval, the slope of the regression line, and thestandard error are then calculated. The results of secondary evaluation(Test 3) are presented in Tables 3A and 3B.

TABLE 1 Primary Screening (Test 1) data for Anticonvulsant Activity andNeurotoxicity in Mice (test compound administered i.p.) RotorodMES^(a,b) ScMET^(a,c) Toxicity^(a,d) Compd 0.5 h 4.0 h 0.5 h 4.0 h 0.5 h4.0 h I-A1-PD7 +(1/1) − +(1/1)^(e) − +(2/4)^(d) − I-A1-PD8 ++(2/3) − − −− − +(1/1) +(1/1) +(1/1) − +(4/4)^(f) − I-A1-PD4 − +++(1/1) − − − −++(1/7) ++(3/3) − − − − +(2/5) +(1/1) − − − − I-AA- − ++(3/3) − − − −MPD12 nd ++(1/3)^(g) nd nd nd nd − +(1/1) − − − − I-CA- − ++(1/3)^(h) −− − − MPD23 − +(1/3) − − − − I-A1-PD13 +(1/1) − +(1/1) − +(1/4) −I-A1-PD5 +(1/1) − +(3/5) − +(3/4)^(i) − I-A1-PD6 +(1/1) − +(1/1) −+(4/4)^(i) − I-A1-PD10 − − − − ++(8/8)^(j) nd I-AA- − − +(1/1) − +(4/4)j− MPD13 I-A1-NOPD1 ++(1/3)^(k) − − − − − +(1/1) − +(1/1) − +(4/4)^(i) −I-A1-NOPD3 − ++(1/3) ++(1/1)^(l) − +++(1/4) − − +(1/1) − − − − I-CA- −++(3/3) − − − − MPD24 − ++(3/3)^(h) − − − − − ++(3/3)^(m) − +(1/1)^(l) −− I-A1-PD15 +(1/1) ++(2/3) − − − − − +(1/1) − − − − I-CA- +(1/1) ++(2/3)− − − − MPD25 − +(1/1) − − − − I-AA- − ++(3/3) − − − − MPD11 +(1/1)+(1/1) − − +(1/4) − ^(a)Key: +++ = activity or toxicity at 30. mg/kg, ++= activity or toxicity at 100 mg/kg,+ = activity or toxicity at 300mg/kg, − = no activity or no toxicity at 300 mg/kg. ^(b)Maximalelectroshock seizure test. ^(c)Subcutaneous pentylenetetrazole seizuretest. ^(d)Neurological toxicity (number of animals exhibitingtoxicity/number of animals tested). ^(e)(number of animalprotected/number of animal tested). nd =not determined. ^(f)Loss ofrighting reflux. ^(g)At 6 hours after dosing. ^(h)At 2 hours afterdosing. ^(i)Unable to grasp rotorod. ^(j)Death. ^(k)At 0.25 hours afterdosing. ^(l)Myoclonic jerks. ^(m)At 6 hours after dosing.

TABLE 2 Screening (Test 2) data for Anticonvulsant Activity andNeurotoxicity in Rats (test compound administered p.o.) Compd Dose(mg/kg) Time (h) MES^(a,b) Toxicity^(c,d) I-A1- 30 0.50 0/4 0/4 PD4 1.001/4 0/4 2.00 3/4 0/4 4.00 4/4 0/4 I-AA- 30 0.50 0/4 0/4 MPD12 1.00 0/40/4 2.00 1/4 0/4 4.00 3/4 0/4 I-CA- 150 2.00 4/4 0/4 MPD23 4.00 4/4 0/46.00 4/4 0/4 8.00 4/4 0/4 I-A1- 50 0.50 0/4 0/4 PD5 1.00 0/4 0/4 2.001/4 0/4 4.00 1/4 0/4 I-A1- 30 0.50 0/4 0/4 NOPD3 1.00 2/4 0/4 2.00 1/40/4 4.00 4/4 0/4 I-CA- 30 0.50 0/4 0/4 MPD24 1.00 2/4 0/4 2.00 3/4 0/44.00 4/4 0/4 I-A1- 30 0.50 0/4 0/4 PD15 1.00 1/4 0/4 2.00 3/4 0/4 4.004/4 0/4 I-CA- 30 0.50 0/4 0/4 MPD25 1.00 3/4 0/4 2.00 4/4 0/4 4.00 2/40/4 I-AA- 30 0.50 0/4 0/4 MPD11 1.00 2/4 0/4 2.00 1/4 0/4 4.00 4/4 0/4^(a)Maximal electroshock seizure test. ^(b)(number of animalprotected/number of animal tested). ^(c)Neurological toxicity.^(d)(number of animals exhibiting toxicity (i.e., atoxia)/number ofanimals tested).

TABLE 3A Screening (Test 3) data for Anticonvulsant Activity (Time toPeak Effect) and Neurotoxicity in Rats (test compound administered p.o.)Time to Peak Effect Dose Time ScMET^(b,c) Toxicity^(d,c) Compd (mg/kg)(h) MES^(a,b) (50 mg/kg) (mg/kg) I-A1- 10 4.0 4/4 PD4 6.0 3/4 8.0 2/4 240/4 30 0.25 2/4 1/4^(f) 0/4 (100) 0.5 2/4 0/4 0/4 (100) 1.0 2/4 2/4 0/4(100) 2.0 2/4 1/4^(g) 0/4 (100) 4.0 4/4 0/4 I-AA- 15 6.0 2/4 MPD12 8.01/4 30 0.5 0/4 1.0 0/4 1/4 0/4 (50) 2.0 1/4 0/4 0/4 (50) 4.0 3/4 0/4 0/4(50) 6.0 4/4 1/4 0/4 (50) 8.0 4/4 2/4 0/4 (50) 24 2/4 0/4 0/4 (50) 8.01/8 (100)^(h) I-A1- 30 0.25 0/8 (500) NOPD3 0.5 0/8 (500) 1.0 0/8 (500)2.0 1/4 0/4 0/8 (500) 4.0 3/4 0/4 0/8 (500) 6.0 3/4 1/4 1/8 (500) 8.04/4 3/4 0/8 (500) 24 3/4 1/4 ^(a)Maximal electroshock seizure test.^(b)(number of animal protected/number of animal tested).^(c)Subcutaneous pentylenetetrazole seizure test. ^(d)Neurologicaltoxicity. ^(e)(number of animals exhibiting toxicity (i.e.,atoxia)/number of animals tested). ^(f)Death following continuousseizure. ^(g)Popcorn effect and continuous seizure activity. ^(h)Mildataxia only.

TABLE 3B Screening (Test 3) data for Anticonvulsant Activity (ED50 andBiological Response and ED₅₀) in Rats (test compound administered p.o.)ED 50 Values and Biological Response 95% Confidence Time Dose IntervalSlope/ Compd (h) (mg/kg) MES^(a,b) ED₅₀ Low/High Std.Er I-A1- 4 1.9 0/8 6.55  3.56/10.72 2.27/0.63 PD4 3.8 4/8  7.5 4/8  15 7/8  30 7/8  I-AA- 67.5 0/8  17.1 9.98/25.8  3.2/0.95 MPD12 15 5/8  30 7/8  60 7/8  I-A1- 83.8 3/8  NOPD3 7.5 3/8  15 4/8  10.1 2.99/17/44 1.61/3.15 30 9/12 608/8  ^(a)Maximal electroshock seizure test. . ^(b)(number of animalprotected/number of animal tested).

I-A1-PD4 is a simple prodrug of lamotrigine. For this prodrug, ED₅₀ forthe MES model was determined to be 6.55 mg/kg and the time to peakeffect was found to be 4.0 h after drug administration at doses of 10 aswell as 30 mg/kg. This compound has shown moderate protection in scMETmodels where one out of four animals were protected at 0.25 h and 2.0 hperiod and two out of four animals were protected at 1.0 h afteradministration of the drug at a dose of 50 mg/kg. For the toxicityanalysis, none of the animals given 100 mg/kg showed signs of toxicity.

I-AA-MPD12 is a mutual prodrug of lamotrigine and gabapentin ethylester. For this compound, ED₅₀ for the MES model was found to be 17mg/kg and the time to peak effect was found to be 6.0-8.0 h at a dose of30 mg/kg and indicated a significant extension protection (2 out of 4animals were still protected) at 24 h after drug administration.Surprisingly, this compound, although less potent than lamotrigine, hasexhibited significant extension in the duration of protection. At 50mg/kg, none of the animals exhibited toxicity. However, at 100 mg/kg,one of eight animals exhibited mild ataxia.

I-AH-NOPD3 is a NO-releasing prodrug of lamotrigine. For this prodrug,ED50 for the MES model was determined to be 10.1 mg/kg and the time topeak effect was found be at 8.0 h at a dose of 30 mg/kg and revealed asignificant extension of protection (3 out 4 animals were stillprotected) even at 24 h after drug administration. Surprisingly, thisprodrug, although less potent than its parent drug, has exhibitedsignificant extension in the duration of protection. At 50 mg/kg, thiscompound has also exhibited significant protection (3 out of 4 animalswere protected at 8 h after drug administration) in scMET rat model. Forthe toxicity analysis, only one in eight animals exhibited toxicity at6.0 h time point at a dose of 500 mg/kg. At other time points (i.e.,0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 8.0 h after drug administration),none of the animals (0/8) exhibited any significant toxicity at the highdose of 500 mg/kg.

Biological Example 2

The pharmacological experiments on NO-releasing aspirin prodrugs werecarried out by following the procedures described herein:

Animals and Procedures:

Male or female Sprague-Dawley rats weighing 150-200 g were used in thestudy. The rats were fed normal standard laboratory chow and maintainedunder standard conditions (room temperature of 22±2° C.; 50±10% relativehumidity; artificial light 06:00 to 18:00). All experimental proceduresmentioned below are approved by institutional animal research committeesand were performed in accordance with standard guidelines for thetreatment of animals.

Sample Preparation and Standard Curve:

HPLC: Waters Allience analytical HPLC equipped with 2996 PDA detectorand Empower software were used to analyze the samples.

HPLC Column: Waters X-Terra RP-18 analytical column, 150×3.9 mm, 5μ.

HPLC Method: Flow: 1 mL/min, detector set at 210 nm and at Maxplot(210-400 nm range). Solvent A: Acetonitrile; Solvent B: 0.1% TFA inwater. Elution method: A linear gradient of 0-100% A.

Plasma samples were processed by transferring 75 μl quantity of bloodinto a test tube containing 250 μl acetonitrile, vortex-mixed andcentrifuged at 1000 g for 5 min. 200 μl of supernatant was then takenand diluted to 2 times with acetonitrile. 100 μl of the sample wasinjected into HPLC for analysis. Salicylate standard curves weregenerated using acetonitrile as solvent in the working range of 1-100μg/ml.

Pharmacokinetic parameters were calculated using WinNonlin software (4.1version). Cmax, Tmax, AUC 0-24, AUC 0-infinity, and T_(1/2)characterized and each curve generated following oral treatment.

In Vitro Plasma Stability:

The rationale is that the prodrugs would be hydrolyzed in-vivo before,during or after absorption to release the corresponding free drugs.Therefore, we tested whether the test compounds (I-C1-NOPD6, I-C1-NOPD4,I-C1-NOPD5A) released parent drug in rat plasma at 37° C. after 30minutes incubation. The compounds were extracted back into acetonitrilewith rigorous vortex. The results suggested that all prodrugs testedexcept I-C1-NOPD6 were found to be converting to the expected metabolite(salicylate) of the parent drug (aspirin) as revealed by HPLC analysis.Even aspirin was completely metabolized to salicylate after 30 minutesof incubation with rat plasma indicating that all the test compoundsreleased aspirin, which in turn converted into salicylate.

Pharmacokinetic Studies:

The oral pharmacokinetics of the test compounds, I-C1-NOPD6, I-C1-NOPD4,I-C1-NOPD5A and I-C1-NOPD5B was done in rats and the release profiles ofsalicylate from these compounds were analyzed by HPLC and the resultswere presented in FIG. 1 and Table 4. Overnight fasted rats were fedwith 35 mg/kg equivalent doses of aspirin and test compounds. Blood wascollected from orbital plexus of test animals at various time points upto 24 hrs. As shown in FIG. 1, the test compounds I-C1-NOPD4 andI-C1-NOPD5B indicated unexpected drug release profiles wherein thesalicylate is released in a sustained and controlled manner startingfrom 1 hour through 12 hours. For I-C1-NOPD5B, the plasma salicylateconcentration was maintained between 50 and 75 μg/ml during thisextended period of over 11 hours. This kind of plasma concentrations ofthe drug can result in significant extension of duration of action. ForI-C1-NOPD4 also, the plasma salicylate concentration was maintainedbetween 35 and 50 μg/mL during an extended period of over 11 hours.Although aspirin absorption (FIG. 1) was highest during 0.5-6.0 hrs(during which period much of the damage to the gastrointestinal tract ofthe subject occurs due to high concentrations of the drug), plasmasalicylate concentration for aspirin and I-C1-NOPD4 were comparableduring the period from 8 through 24 hours. Such sustained releaseprofile of active drug from the prodrug is expected to cause negligibleor insignificant gastrointestinal damage as the plasma concentration ofthe drug never reaches to the toxic levels. Similar release profile wasobserved with I-C1-NOPD5A but for a shorter period of time.Unexpectedly, we have also observed as recorded in Table 4, nearly equaldrug AUC values for aspirin and I-C1-NOPD5B (i.e., 923.63±182.08 foraspirin vs 951.98±11.58 for I-C1-NOPD5B) which indicates that theprodrug is as bioavailable as its parent drug, but prodrug does notcause gastric damage. Surprisingly, neither the prodrug nor thesalicylate was found in the plasma of the animals fed with I-C1-NOPD6(data not included in the graph) at any point of time tested, thereasons for which are not known.

TABLE 4 Comparison of pharmacokinetic parameters of aspirin and itsnitro derivatives Parameters* Aspirin I-C1-NOPD4 I-C1-NOPD5A I-C1-NOPD5BCmax (μg/mL) 98.67 ± 12.64 53.24 ± 6.39 50.14 ± 10.12 66.08 ± 3.31 Tmax(h) 0.50 ± 0.00  4.66 ± 0.57 3.00 ± 0.57  4.00 ± 0.81 AUC_(0-24 h) (h ·μg/ml) 905.84 ± 173.14 749.36 ± 69.38 557.80 ± 97.65  922.89 ± 12.50AUC_(0-α) (h · μg/ml) 923.63 ± 182.08 772.17 ± 75.68 565.30 ± 96.78 951.98 ± 11.58 T_(1/2) (h) 3.56 ± 0.42  3.98 ± 0.25 3.35 ± 0.32  4.14 ±0.24 *The data values are mean ± SEM, n = 3-4Ulcerogenic Activity:

Gastrointestinal ulceration is a serious side effect associated withNSAIDs. The clinical uses of potent NSAIDs are greatly limited by itsgastrointestinal toxicity. We tested ulcerogenic potential of the testcompounds, I-C1-NOPD6, I-C1-NOPD4, I-C1-NOPD5A, and I-C1-NOPD5B in rats.Overnight fasted rats were given orally 100 mg/kg equivalent doses ofaspirin and prodrugs (in the case of I-C1-NOPD5A and I-C1-NOPD5B, 200mg/kg equivalent doses were administered). The animals were sacrificedat 3 hours after drug administration. Stomachs of treated rats wereseparated, perfused with 10 ml of 2% formalin, and then cut open overthe greater curvature. The severity of the mucosal damage was thenassessed on the basis of size (area) of the observed ulcers undersurgical microscope with a square grid as per the established procedure(Takeuchi et al., J. Pharmacol. Exp. Ther. 1998, 286 (1), 115-121).Interestingly, none of the animals treated with the test compoundsshowed any signs of development of ulcers. However, severe haemorrhagiclesions (Mean±S.E.M.: 2.7±0.9 mm²) were seen in aspirin treated rats.

Anti-Inflammatory Activity:

Anti-inflammatory activity of test compounds was measured incarrageenan-induced rat paw edema model (Takeuchi et al., J. Pharmacol.Exp. Ther. 1998, 286 (1), 115-121). The activity of aspirin and testcompounds (75 mg/kg equivalent dose of aspirin) is shown in Table 5.Aspirin at 75 mg/kg, p.o. exhibited anti-inflammatory activity from 1 hrthrough 6 hr with peak maximal activity at 4 hr. I-C1-NOPD4 showedsignificant activity during the first two hours after drugadministration but its activity was not as good as that of aspirin from2 hr through 6 hr. Surprisingly, I-C1-NOPD5A showed negligibleanti-inflammatory activity at any time point tested (data notincorporated). We have not yet evaluated I-C1-NOPD5B in this efficacytest.

TABLE 5 Rat paw edema (% inhibition) Mean ± SEM, n = 6 Compound 1 hour 2hour 4 hour 6 hour Aspirin 31.0 ± 7.2  52.5 ± 3.4  60.7 ± 6.9 42.8 ± 6.9I-C1-NOPD4 42.4 ± 13.3 44.9 ± 12.9 24.3 ± 7.7  8.6 ± 5.1

The results indicate the following:

-   -   1. Sustained release of the active drug over a period of 10-11        hours, which is good for twice daily dosage regimen, and    -   2. Exceptional gastrointestinal safety even at high equivalent        doses of prodrugs compared to aspirin, which caused severe        ulcers at equivalent doses.

1. A compound of formula (I) or pharmaceutically acceptable saltsthereof:

wherein, a is 0; B is S—S; A is CH₂; A¹ is CH₂; D¹ represents atherapeutic agent comprising one or more of the functional groupsselected from the group consisting of —NHR¹, —CONHR¹, —SO₂NHR¹,—OSO₂NHR¹, N(R¹)C(═O)NHR¹ and —N(R¹)SO₂NHR¹; wherein the N atom in saidfunctional groups is either a part of or directly attached to L¹; D²represents a therapeutic agent comprising one or more of the functionalgroups selected from the group consisting of —OH, —SH, and —CO₂H,wherein the O of —OH or the S of —SH or the C(═O) of the —C(═O)OH groupis either a part of or directly attached to L²; E is CH₂; L¹ representsNR¹—(CO)—O and L² represents O—(CO)—; R¹ represents H or a bond to theresidue of the therapeutic agent at an atom other than the atom to whichN is attached.
 2. The compound according to claim 1, wherein thecompound is selected from:


3. A pharmaceutical composition comprising a therapeutically effectiveamount of the compound of claim 1 or a pharmaceutically acceptable saltthereof; and one or more pharmaceutically acceptable carriers, vehiclesor diluents.
 4. A pharmaceutical composition comprising atherapeutically effective amount of the compound of claim 2, or apharmaceutically acceptable salt thereof; and one or morepharmaceutically acceptable carriers, vehicles or diluents.
 5. Thecomposition of claim 3, comprising therapeutically effective amount ofpairs of drugs selected from: paclitaxel and doxorubicin, paclitaxel andmitomycin C, paclitaxel and 9-aminocamptothecin,3-aminopyridine-4-methyl-2-carboxaldehyde thiosemicarbazone (3-AMP) andpaclitaxel, CC-1065 and paclitaxel, CC-1065 and doxorubicin, CC-1065 andmitomycin C; trans-resveratrol [(E)-3,4′,5-trihydroxystilbene) anddoxorubicin, trans-resveratrol [(E)-3,4′,5-trihydroxystilbene) andmitomycin C, edatrexate and paclitaxel, cephalosporin and paclitaxel,paclitaxel and gemcitabine, amoxicillin and clavulanic acid, ampicillinand clavulanic acid, amlodipine and lovastatin, amlodipine andpravastatin, amlodipine and fluvastatin, amlodipine and atorvastatin,amlodipine and simvastatin, metformin and nateglinide, metformin andlovastatin, metformin and pravastatin, metformin and fluvastatin,metformin and atorvastatin, metformin and simvastatin, pseudoephedrineand fexofenadine, pseudoephedrine and cetirizine, salbutamol andipratropium bromide; mometasone and formoterol, mometasone andsalmeterol; fluticasone and formoterol, fluticasone and salmeterol,budesonide and formoterol, budesonide and salmeterol, diclofenac andmisoprostol, diclofenac and omeprazole, diclofenac and lansoprazol,diclofenac and rabeprazole, diclofenac and leminoprazole, diclofenac andpantoprazole, acetaminophen and chlorzoxazone, acetaminophen andmephenoxalone, zidovudine and lamivudine, stavudine and lamivudine,dideoxyinosine and lamivudine, emtricitabine and penciclovir,emtricitabine and famciclovir; acyclovir and deoxycholate, andlamivudine and efavirenz.
 6. The compound according to claim 1, whereinD¹ and D² are therapeutic agents independently selected from the groupconsisting of: sedatives, hypnotics, antidepressants, antipsychotics,antimanics, analgesics, antipyretics, antimigraine agents,anticonvulsants, drugs used in parkinsonism and movement disorders,drugs used for treating dementia, anti-emetics, drugs used for treatingvertigo, CNS stimulants activators, antiinfective eye preparations,anti-inflammatory, anti-allergic preparations, antiglucoma drugs,preparations to cure eye diseases, aural preparations, nasalpreparations, oropharyngeal preparations, anti-arrhythemic drugs,antihypertensives, alfa/beta-blockers, ACE inhibitors, angiotensin IIreceptor antagonists, diuretics, anti-anginals, nitrates, calciumchannel blockers, drugs for cardiac failure and shock, vasodilators,coagulants, anticoagulants, thrombolytics, antiplatelet drugs,respiratory stimulants, antitussives, expectorants, mucolytics,decongestants, antihistamine agents, anti-asthmatics; antiulcer,antisecretory drugs, H₂ receptor antagonists, proton pump inhibitors,prostaglandin analogues, antacids, antispasmodics, drugs modifyingintestinal motility, antidiarrhoeals, antimotility drugs, antimicrobialdrugs, drugs acting on gall bladder, urinary antiinfectives, diuretics,urinary analgesics, antispasmodics, antiinfective drugs acting onurethra and vagina, drugs acting on uterus, drugs for prostatichypertrophy, alfa blockers, antiandrogens, drugs for erectiledysfunction, spermicidals, nonhormonal contraceptives, emollients,keratolytics, topical antiinfectives, topical antifungals, topicalparasiticidals, topical steroids, topical drugs for acne vulgaris, drugsfor psoriasis, pigmentation disorders, and antiseborrhoeics, nonsteroidal anti inflammatory drugs (NSAIDs), COX-2 inhibitors,antiarthritic agents, immunosuppressants, topical analgesics, musclerelaxants, neuromuscular drugs, antianaerobics, antitubercular drugs,antileprosy drugs, antifungals, antiprotozoals, anthelminthics,antiinfective drugs, antimalarials, antivirals, anabolics, androgenicsteroids, corticosteroids, oestrogens, progestogens and hormonalcontraceptives, fertility agents, trophic hormones and related drugs,thyroid and antithyroid drugs, antidiabetics and hyperglycaemics,vitamins, amino acids, anti-obesity drugs, hypolipidaemic drugs, fibricacid derivatives, statins, HMG CoA reductase inhibitors, drugs used forgout, drugs affecting bone metabolism, bisphosphonates, anticancer orantineoplastic drugs, cytotoxic antibiotics, antimetabolites,topoisomerase I inhibitors, cytotoxic immunosuppressants,immunostmulants, cytoprotectives, amifostine, oestrogens, progestogens,hormone antagonists, non-sedative antihistamins, sedative histamines,histamine receptor blockers, local anaesthetics, intravenousanaesthetics, inhalation anaesthetics, and muscle relaxants.
 7. Thecompound according to claim 1, wherein D¹ and D² are therapeutic agentsindependently selected from the group consisting of: penicillinantibiotics, cephalosporin antibiotics, quinolone, fluoroquinoloneantibiotics, macrolide antibiotics, chloramphenicol, tetracylineantibiotics, sulfonamides, metronidazole, nicotinic acid drugs,alkylating agents, cytarabine, fludarabine, 5-fluorouracil,mercaptopurine, thioguanine, vinca alkaloids, etoposide, taxanes,cetirizine, desloratadine, terfenadine and fexofenadine.
 8. A method oftreating a disease where a chronic, sustained and selective release ofthe constituent therapeutic agent is beneficial; comprisingadministering to a mammal or a human in need of the treatment atherapeutically effective amount of the compound of claim
 1. 9. A methodof treating a disease in a human or mammal where a chronic, sustainedand selective release of the constituent therapeutic agent isbeneficial; comprising administering to said mammal a therapeuticallyeffective amount of the pharmaceutical composition as claimed in claim3.
 10. The method of claim 8, wherein the disease is selected from thegroup consisting of the diseases of central nervous system, eye, ear,nose and oropharynx, cardiovascular system, respiratory system,gastrointestinal tract system, genitourinary system, skin,musculoskeletal system, endocrine system, metabolism and neoplasticdisorders, infectious diseases, allergy and immunology, and foranaesthetic, analgesic and surgical needs in a mammal.
 11. The method ofclaim 9, wherein the disease is selected from the group consisting of:the diseases of central nervous system, eye, ear, nose and oropharynx,cardiovascular system, respiratory system, gastrointestinal tractsystem, genitourinary system, skin, musculoskeletal system, endocrinesystem, metabolism and neoplastic disorders, infectious diseases,allergy and immunology, and for anaesthetic, analgesic and surgicalneeds in a mammal.
 12. A process for the preparation of the compoundaccording to claim 1, wherein D¹ and D² independently represent atherapeutic agent containing one or more functional groups selected from—OH, —SH or —NHR¹ provided that when D¹ is a therapeutic agentcontaining NHR¹, then D² is a therapeutic agent containing a hydroxyl-or sulfhydryl-group; wherein said process comprises the steps of: a)monoprotection of bis-(2-hydroxyethyl)disulphide (SL-1) with anappropriate hydroxylprotecting group (PG) to yield the correspondingmonoprotected intermediate (LI-1x);

b) converting said intermediate (LI-1x) to an activated formylintermediate (LI-1xy) by treating with phosgene;

c) reacting the intermediate LI-1xy obtained in the step b) with anappropriate therapeutic agent (D¹) in the presence of a base and asolvent to obtain the intermediate compound of the following formula;

d) subjecting the intermediate obtained in step c) above to adeprotection step to remove the hydroxyl protecting group to yield anintermediate of the following formula;

e) converting the resulting intermediate as obtained in step d) to anactivated formyl intermediate of the following formula by treating withphosgene,

f) reacting said intermediate obtained in step d) with an appropriatetherapeutic agent (D²) in the presence of a base and a solvent to yieldthe compound of formula I; or said process comprises the steps of: a)converting an appropriate therapeutic agent (D¹) to its isocyanatederivative or its carbamoyl derivative or its formyl derivative; b)treating the isocyanate derivative or the carbamoyl derivative or theformyl derivative of the therapeutic agent D¹ with the monoprotectedlinker intermediate LI-1x in the presence of a base and a solvent toyield the intermediate;

c) subjecting the resulting intermediate of step (b) to deprotection toyield the corresponding intermediate having a free terminal hydroxylgroup; d) converting an appropriate therapeutic agent D² to itsisocyanate derivative or its carbamoyl derivative or its formylderivative under appropriate reaction conditions; e) reacting theintermediate obtained in step (c) above with the isocyanate derivativeor the carbamoyl derivative or the formyl derivative of the therapeuticagent D² as obtained in step (d) above in the presence of a base and asolvent to yield the compound of formula I; or said process comprisesthe steps of a) converting an appropriate therapeutic agent (D¹) to itsisocyanate derivative or its carbamoyl derivative or its formylderivative; b) treating the isocyanate derivative or the carbamoylderivative or the formyl derivative of the therapeutic agent D¹ asobtained in step (a) above with the disulfide linker SL-1 in thepresence of a base and a solvent to yield the corresponding intermediatewhich on removal of the protection group (PG) to yield the correspondingintermediate having a free hydroxyl group; c) converting an appropriatetherapeutic agent D² to its isocyanate derivative or its carbamoylderivative or its formyl derivative; d) reacting the intermediateobtained in step (b) above with the isocyanate derivative or thecarbamoyl derivative or the formyl derivative of the therapeutic agentD² obtained in step (c) above in the presence of a base and a solvent toyield compound of formula I.
 13. A process for the preparation of thecompound according to claim 1, wherein D¹ and D² independently representa therapeutic agent containing —COOH group provided that D¹ and D² aredifferent therapeutic agents; wherein said process comprises the stepsof: (a) converting both the therapeutic agents D¹ and D² to theircorresponding acyl chloride or imidazolide derivatives by a standardknown method; (b) reacting the reactive acyl chloride or imidazolidederivatives obtained in step (a) with 1.5 to 3.0 fold excess of thedisulfide linker SL-1 in the presence of a base and a solvent to yieldthe following intermediate containing a free terminal hydroxyl group;

(c) reacting the intermediate obtained in step (b) above with the acylchloride or imidazolide derivative of the therapeutic agent D² in thepresence of a base and a solvent to yield the compound of formula I; orsaid process comprises the steps of: (a) reacting the therapeutic agentD¹ with 1.5 to 3.0 fold excess of the disulfide linker SL-1 in thepresence of a coupling agent selected from selected fromN,N′-dicyclohexylcarbodiimide (DCC), 4-dimethylaminopyridine (DMAP) ortriethylamine (TEA) in a solvent to obtain the intermediate containing afree terminal hydroxyl group; (b) reacting the intermediate obtained instep (a) with a therapeutic agent D² in the presence of a coupling agentN,N′-dicyclohexylcarbodiimide (DCC), 4-dimethylamino-pyridine (DMAP) ortriethylamine (TEA) in a solvent to yield the compound of formula I; or,said process comprises the steps of: (a) converting the therapeuticagents D¹ and D² into their carboxylate metal salts (D¹-COO⁻)_(n) M^(n+)and (D²-COO⁻)_(n) M^(n+) (wherein, M⁺=Na⁺, K⁺, Cs⁺ or Ca⁺⁺; n 1-2)respectively by a known method; (b) converting the disulfide linker SL-1to its mono bromide (LI-2a) and dibromide (LI-3a) intermediates by aknown method;

(c) reacting the carboxylate metal salt (D¹-COO⁻)_(n) M^(n+) obtained instep (a) with either mono bromide LI-2a or with 1.5 to 3.0 fold excessof dibromide LI-3a in a solvent to yield the corresponding intermediatewith free terminal alcohol or bromide group;

(d) reacting the carboxylate salt (D²-COO⁻)_(n) M^(n+) obtained in step(a) with the intermediate having a terminal bromide group obtained instep (c) in a suitable solvent to yield the compound of formula I.
 14. Aprocess for the preparation of the compound according to claim 1,wherein D¹ is a therapeutic agent containing —COOH group and D²represent a therapeutic agent containing —OH, —SH or —NHR¹ wherein R¹ asdefined in claim 1; said process comprising the steps of: (a) preparingan intermediate containing a free terminal hydroxyl group on the linkerfrom the intermediate which is obtained by coupling of the therapeuticagent D¹ containing —COOH group and the disulfide linker (SL-1); (b)reacting the intermediate obtained in step (a) with an appropriatetherapeutic agent D² containing one or more of the functional groupselected from —OH, —SH or —NHR¹ to yield the mutual prodrug compound offormula I or said process comprising the steps of: (a) preparing anintermediate containing a free terminal hydroxyl group on the linkerfrom the intermediate which is obtained by coupling of the therapeuticagent D² containing —OH, —SH or —NHR¹; wherein R¹ as defined in claim 1;and the disulfide linker (SL-1); (b) reacting the intermediate obtainedin step (a) with a therapeutic agent D¹ containing —COOH group undersuitable reaction conditions to yield the mutual prodrug compound offormula I; or said process comprises the steps of: (a) converting atherapeutic agent D¹ containing —COOH group into its acid chloride byreacting with thionyl chloride or oxalyl chloride and treating theresulting acid chloride derivative of D¹ with ammonia to yield thecorresponding amide derivative (D¹-C(═O)NH₂) of the therapeutic agent;(b) treating the amide derivative obtained in step (a) with oxalylchloride to yield the corresponding acyl isocyanate derivative(D¹-C(═O)N═C═O) of D¹; or said acyl isocyanate derivative(D¹-C(═O)N═C═O) of D¹ can be prepared by treating the acid chloride(D¹-COCl) derivative of D¹ with silver isocyanate; (c) reacting theresulting acyl isocyanate (D¹-C(═O)N═C═O) derivative with 2-3equivalents of the disulfide linker (SL-1) to yield the followingintermediate with free terminal hydroxyl group on the linker;

 and (d) reacting the intermediate obtained in step (d) with atherapeutic agent D² containing either an —OH, —SH, —COOH or —NHR¹ toyield compound of formula I.
 15. A process for the preparation of thecompound according to claim 1, wherein D¹ and D² represent a therapeuticagent containing —OH wherein said D¹ and D² may be the same or differenttherapeutic agents; said process comprising the steps of: (a)monoprotecting the compound having formula, R¹HNCH₂CH₂NHR¹ to obtain thecorresponding Boc protected derivative, R¹HNCH₂CH₂N(Boc)R¹; (b)converting a therapeutic agent D¹ containing —OH group to its formylderivative [D¹-O—C(═O)-LG, wherein, LG=a leaving group] by treating withphosgene or its equivalent in the presence of a base and a solvent; (c)reacting the intermediate R¹HNCH₂CH₂N(Boc)R¹ obtained in step (a) withthe intermediate D¹-O—C(═O)-LG obtained in step (b) in the presence of abase and a solvent to yield the intermediate D¹-O—C(═O)—(R¹)NCH₂CH₂N(Boc)R¹; (d) treating the resulting intermediateD¹-O—C(═O)—(R¹)NCH₂CH₂N(Boc)R¹ by treatment with trifluoroacetic acid(TFA) to remove the Boc group and to obtain the intermediate TFA salt[D¹-O—C(═O)—(R¹)NCH₂CH₂NHR¹.TFA]; (e) reacting the intermediate obtainedin step (d) with a linker (LI-1xy) of the following formula;

 in the presence of a base and a solvent to yield an intermediate, whichupon removal of the protecting group by a standard method provided anintermediate containing a free terminal hydroxyl group on the linker;(f) reacting the intermediate obtained in step (e) above with phosgenein the presence of a base and a solvent to its corresponding formylderivative; (g) converting the therapeutic agent D² into an intermediatehaving the following formula by following the same steps (a) to (d):

(h) reacting the intermediates obtained in steps (f) and (g) in presenceof a base and a solvent to yield to compound of formula I.
 16. A processfor the preparation of the compound according to claim 1, wherein D¹ andD² represent a therapeutic agent containing —OH, —SH or —NHR¹ group;wherein said D¹ and D² may be the same or different therapeutic agents;said process comprising the steps of: (a) converting a therapeutic agentD¹ to its isocyanate derivative or carbamoyl derivative or formylderivative under suitable reaction conditions; (b) treating theresulting isocyanate derivative or carbamoyl derivative or formylderivative obtained in step (a) with 2-(2-aminoethyl)disulfanyl)-ethanol(SL-2) in the presence of a base and a solvent to obtain an intermediatecontaining a terminal free hydroxyl group; (c) converting a therapeuticagent D² to its isocyanate derivative or carbamoyl derivative or formylderivative under suitable reaction conditions; and (d) reacting theintermediate obtained in step (b) isocyanate derivative or carbamoylderivative or formyl derivative of the therapeutic agent D² obtained instep (c) in the presence of a base and a solvent to yield the compoundof formula I.